Therapeutic Peptides as Precision Medicine for Longevity, Metabolism, and Tissue Repair

Keywords: Therapeutic Peptides, GLP-1 Receptor Agonists, Growth Hormone Secretagogues, Tissue Regeneration, Longevity, Metabolic Health

Introduction

Peptide-based therapeutics have a history stretching back to the isolation of insulin by Banting and Best in 1921, yet the past two decades have witnessed an extraordinary renaissance in their clinical development. As of 2024, more than 80 peptide drugs have received global regulatory approval, and an estimated 200 to 300 peptide compounds are in active clinical development, with the global therapeutic peptide market valued at approximately USD 40 billion and projected to exceed USD 80 billion by 2030. This resurgence is driven by three converging forces: advances in solid-phase peptide synthesis enabling cost-effective production of complex sequences; chemical modifications that overcome the historical limitation of rapid proteolytic degradation; and a growing appreciation that peptides occupy a privileged pharmacological niche, smaller than biologics, yet more target-selective and less toxic than many small-molecule drugs [1-4].

Therapeutic peptides are conventionally defined as amino acid chains comprising 2 to 50 residues, with a molecular weight range of approximately 200 to 5,000 daltons. This molecular size confers several biopharmaceutical advantages: exquisite receptor selectivity arising from the structural mimicry of endogenous signaling molecules; a metabolic breakdown profile yielding naturally occurring amino acids with low systemic toxicity; and, in contrast to protein biologics, a reduced propensity for immunogenicity. Despite these intrinsic advantages, peptide therapeutics face notable delivery challenges, including susceptibility to gastrointestinal proteolysis limiting oral bioavailability, rapid renal clearance shortening plasma half-lives, and cellular membrane impermeability restricting access to intracellular targets. Medicinal chemistry innovations, including lipidation (as in semaglutide and liraglutide), DAC (drug affinity complex) albumin binding (CJC-1295), cyclisation, N-methylation, and incorporation of non-natural amino acids, have substantially addressed these barriers [2-7].

The clinical landscape of therapeutic peptides spans diverse areas including metabolic disease, oncology, infectious disease, endocrinology, and the burgeoning field of longevity medicine. In the context of a global epidemic of obesity, type 2 diabetes, and metabolic syndrome affecting over 1.9 billion adults worldwide, glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as arguably the most clinically impactful peptide drug class in recent pharmacological history. Simultaneously, growing interest in preventive medicine and healthy longevity has driven investigation of peptides targeting growth hormone signaling, tissue repair, immune senescence, and telomere biology [8-10].

This comprehensive review provides a structured overview of the major therapeutic peptide classes relevant to longevity, metabolic health, and preventive medicine. For each category, we summarize mechanism of action, key clinical trial evidence, safety profiles, and regulatory status, using a format designed to serve both clinicians and researchers navigating an increasingly complex and commercially active field [1,2]

Biochemistry of Therapeutic Peptides: Structure, Stability, and Receptor Interactions

Structural Fundamentals

Peptides are linear polymers of alpha-amino acids joined by amide (peptide) bonds. The primary structure, the specific sequence of amino acid residues, dictates secondary structure (alpha-helices and beta-sheets), which in turn determines three-dimensional conformation and ultimately receptor-binding geometry. For peptide therapeutics, the pharmacophoric elements are typically constrained to the three-to-seven residues that make direct contact with the receptor binding domain, while flanking residues serve structural or pharmacokinetic functions [3,5].

Modifications to the native peptide backbone substantially alter pharmacokinetic properties. Lipidation, the covalent attachment of fatty acid chains, enables non-covalent binding to circulating albumin, extending half-life from minutes to hours or days, as exploited in liraglutide (C16 fatty acid) and semaglutide (C18 fatty diacid). The DAC technology utilised in CJC-1295 uses a maleimido-propionamide linker that forms a stable thioether bond with endogenous albumin cysteine-34, extending the half-life of this GHRH analog from minutes to approximately six to eight days. Cyclisation, forming a disulfide or amide bond between the N- and C-termini, confers conformational rigidity, proteolytic resistance, and improved receptor selectivity, as demonstrated in cyclic somatostatin analogs [5-7].

Receptor Pharmacology

Therapeutic peptides exert their biological effects primarily through G protein-coupled receptors (GPCRs), which account for approximately 35% of all drug targets, or through nuclear hormone receptors, ion channels, or intracellular enzyme modulation. GLP-1, GIP, glucagon, and ghrelin all signal through class B GPCRs, which undergo large-scale conformational rearrangements upon peptide binding, coupling to Gs proteins and elevating cyclic AMP as the primary second messenger. The selectivity of peptide agonists at these receptors is determined by the precise fit of the peptide’s N-terminal activation domain into the receptor’s transmembrane domain, while the C-terminal domain anchors the peptide at the extracellular loops [11,12].

Peptides targeting growth hormone secretion, including GHRH analogs and ghrelin receptor agonists, modulate hypothalamic-pituitary signaling to restore physiological pulsatile GH release, an architecture that preserves somatostatin-mediated feedback and thereby minimizes the risk of GH excess. By contrast, exogenous recombinant growth hormone administration suppresses endogenous GH pulse amplitude and disrupts feedback regulation, a key safety distinction relevant to clinical prescribing [13,14].

Classification Framework

Therapeutic peptides can be classified by multiple orthogonal frameworks: by molecular origin (endogenous, synthetic, or semi-synthetic); by mechanism of action (agonist, antagonist, partial agonist); by therapeutic category; or by regulatory and evidence tier. For the purposes of this review, we adopt a mechanistic-and-target classification, grouping peptides into six clinically coherent categories relevant to longevity and preventive medicine: (1) metabolic and GLP-1 receptor agonists; (2) growth hormone secretagogues and GHRH analogs; (3) tissue repair and regenerative peptides; (4) immunomodulatory peptides; (5) neuroprotective and cognitive peptides; and (6) longevity and anti-aging bioregulators. An additional seventh category, peptides for sexual function is discussed separately given its distinct neurobiological basis [1,2].

Category	Representative Agents	Primary Mechanism	Evidence Tier
GLP-1/Metabolic	Semaglutide, Tirzepatide, Liraglutide, Retatrutide, Cagriliptide	GLP-1/GIP/Glucagon receptor agonism	I (Multiple Phase 3 RCTs)
GHRH/GH Secretagogues	Cjc-1295, Ipamorelin, Sermorelin, Teamorelin	GHRH receptor agonism; GHS-R1a agonism	II–III (Phase 2 trials; FDA-approved: Tesamorelin)
Tissue repair	BPC-157, TB-500, GHK-Cu	NO signalling, actin dynamics, gene expression	IV (Preclinical dominant; no Phase 3 RCTs)
Immunomodulatory	Thymosin Alpha-1, LL-37, Cibinetide	TLR agonism, cathelicidin, IRR pathway	II–III (Thymosin Alpha-1: approved in >35 countries)
Neuroprotective	Selank, Semax, Cerluten	BDNF upregulation, GABA modulation, ACTH analog	III (Approved in Russia; limited Western RCTs)
Longevity/ Anti-Aging	Epithalon, Flamipretide	Telomerase activation, cardiolipin stabilisation	III–IV (Phase 2 for Elamipretide; preclinical/observational for Epithalon)
Sexual Function	PT-141 (Bremelanotide)	Melanocortin MC3R/MC4R agonism (CNS)	I (FDA-approved: Vyleesi 2019)

Table 1. Classification Of Therapeutic Peptides By Category, Mechanism, And Evidence Tier

GLP-1 Receptor Agonists and Metabolic Peptides

The Incretin axis and Pharmacological Targets

Glucagon-like peptide-1 (GLP-1) is a 30-amino-acid incretin hormone secreted by intestinal L-cells in response to nutrient ingestion. It exerts pleiotropic effects through the GLP-1 receptor, a class B GPCR expressed on pancreatic beta cells, cardiac myocytes, renal tubular cells, and multiple brain regions including the hypothalamus and nucleus tractus solitarius. The principal metabolic actions of GLP-1 include glucose-dependent stimulation of insulin secretion, suppression of glucagon, delayed gastric emptying, and central appetite reduction through hypothalamic satiety circuits. Native GLP-1 has a plasma half-life of less than two minutes due to rapid cleavage by dipeptidyl peptidase-4 (DPP-4), necessitating structural modifications to create viable pharmacological agents [6,8,12].

The discovery that glucose-dependent insulinotropic polypeptide (GIP) and glucagon receptors could be co-targeted with GLP-1 receptor activation to achieve greater metabolic efficacy than GLP-1 monotherapy has driven the development of multi-receptor agonists, culminating in dual GLP-1/GIP agonists (tirzepatide) and triple GLP-1/GIP/glucagon agonists (retatrutide). GIP receptor co-activation appears to enhance GLP-1 receptor-mediated effects through mechanisms that include increased beta-cell insulin secretory capacity, adipocyte lipid metabolism modulation, and complementary hypothalamic appetite suppression pathways [15,16].

Semaglutide

Semaglutide is a GLP-1 receptor agonist structurally modified from native GLP-1 through substitution of alanine at position 8 with alpha-aminoisobutyric acid (conferring DPP-4 resistance), and attachment of a C18 fatty diacid chain via a linker to lysine at position 26, enabling once-weekly subcutaneous dosing through albumin binding. The STEP trial program established semaglutide 2.4 mg once weekly as a landmark obesity pharmacotherapy. The STEP 1 trial demonstrated mean body weight reduction of 14.9% over 68 weeks versus 2.4% with placebo in 1,961 adults with BMI ≥30 or ≥27 with weight-related comorbidities. Cardiovascular outcomes were assessed in the SELECT trial, which enrolled 17,604 adults with pre-existing cardiovascular disease and overweight/obesity but without diabetes. Semaglutide 2.4 mg significantly reduced the composite primary endpoint of MACE such as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke by 20% (hazard ratio 0.80; 95% CI 0.72–0.90; p<0.001). Emerging evidence also supports GLP-1 receptor agonism as a neuroprotective strategy; semaglutide is currently under Phase 3 evaluation for Parkinson’s disease and early Alzheimer’s disease [6,7,18,19].

Tirzepatide

Tirzepatide represents a novel class of dual GIP/GLP-1 receptor agonist, a single synthetic peptide that simultaneously activates both incretin receptors with differential potency, mimicking postprandial incretin biology more completely than GLP-1 monotherapy. The SURPASS trial series demonstrated superior glycaemic control versus GLP-1 monotherapy: the SURPASS-2 trial showed tirzepatide 15 mg achieved HbA1c reduction of 2.46% versus 1.86% for semaglutide 1 mg (p<0.001). For obesity, the SURMOUNT-1 trial enrolled 2,539 adults with obesity and demonstrated tirzepatide 15 mg produced a mean weight reduction of 20.9% versus 3.1% with placebo at 72 weeks, the largest randomized trial weight loss outcome recorded at time of publication. Direct comparison with semaglutide in the SURMOUNT-5 trial confirmed tirzepatide superiority, with 47% greater odds of achieving ≥25% weight loss versus semaglutide 2.4 mg [15,16,20,21].

Liraglutide, Retatrutide, Cagrilintide, and AOD-9604

Liraglutide, the first long-acting GLP-1 receptor agonist approved for obesity management (Saxenda), demonstrated 5–8% weight loss in the SCALE Obesity and Prediabetes trial, significantly less than later agents, limiting its current utility in weight management as more efficacious options become available. The LEADER cardiovascular outcomes trial established liraglutide’s cardioprotective effect a 13% reduction in MACE in adults with type 2 diabetes and established cardiovascular disease. Retatrutide, a triple GLP-1/GIP/glucagon receptor agonist, demonstrated weight reductions up to 24.2% at 48 weeks in Phase 2 trials published in the New England Journal of Medicine in 2023, entering Phase 3 evaluation for obesity and type 2 diabetes. Cagrilintide, a long-acting amylin analog that targets amylin receptors in the hindbrain, reduces caloric intake through a mechanism distinct and complementary to GLP-1 receptor agonism. In the REDEFINE 1 Phase 3 trial, the combination of cagrilintide 2.4 mg and semaglutide 2.4 mg (CagriSema) demonstrated 22.7% weight reduction over 68 weeks, approaching surgical weight loss outcomes. AOD-9604, a synthetic C-terminal fragment of human growth hormone (residues 176–191), promotes lipolysis through beta-adrenergic receptor activation without elevating IGF-1, representing a mechanistically distinct approach to adiposity reduction that completed Phase 2 clinical evaluation for obesity [22-26].

Growth Hormone-Releasing Hormone Analogs and Secretagogues

Somatotropic Axis Physiology and Decline with Aging

Growth hormone (GH) is secreted by pituitary somatotrophs in a pulsatile, predominantly nocturnal pattern regulated by the interplay between hypothalamic growth hormone-releasing hormone (GHRH) and somatostatin. GH stimulates hepatic production of insulin-like growth factor-1 (IGF-1), which mediates most anabolic effects including lean body mass accretion, bone mineralization, and lipolysis. After peak somatotropic axis activity in late adolescence and early adulthood, GH secretion declines at approximately 14% per decade, a phenomenon termed somatopause. This decline is associated with increased visceral adiposity, reduced muscle mass (sarcopenia), decreased bone mineral density, impaired sleep architecture, and reduced physical capacity, a cluster of changes highly relevant to healthy ageing strategies [13,14,27].

GHRH Analogs: Sermorelin, CJC-1295, and Tesamorelin

Sermorelin, comprising the first 29 amino acids of endogenous GHRH, was the first synthetic GHRH analog approved by the FDA (Geref, 1997) for the diagnosis and treatment of GH deficiency in children. Its short half-life (~10–20 minutes) requires daily subcutaneous injection and results in a GH pulse pattern closely approximating physiological release. Clinical evidence supports modest IGF-1 elevation, improvements in sleep architecture, and favourable body composition effects, though most studies in adults are small and short-term. CJC-1295 with DAC (drug affinity complex) extends the GHRH (1-29) sequence’s half-life to approximately six to eight days through covalent albumin binding, enabling once-to-twice-weekly dosing. A dose-ranging study by Teichman et al. demonstrated that single doses of CJC-1295 produced dose-dependent increases in mean plasma GH concentration (by 2–10-fold) and sustained IGF-1 elevations (1.3–1.9-fold above baseline) for six to eight days. Tesamorelin, a stabilised synthetic analog of GHRH (1-44) is the only GHRH analog with current FDA approval, indicated for visceral adiposity in HIV-infected patients with lipodystrophy. Phase 3 trials demonstrated statistically significant reductions in visceral adipose tissue of approximately 15–20% compared with placebo after 26 weeks [7,27-29].

GH Secretagogues: Ipamorelin, GHRP-2, GHRP-6, and Hexarelin

Growth hormone secretagogues (GHSs) act through the ghrelin receptor (GHS-R1a), a hypothalamic and pituitary GPCR distinct from the GHRH receptor, providing a complementary route to GH pulse amplification. Ipamorelin is a synthetic pentapeptide GHS-R1a agonist that selectively stimulates GH release without co-stimulating the hypothalamic-pituitary-adrenal axis, in contrast to earlier GHSs such as GHRP-2 and GHRP-6, which produce clinically significant elevations in cortisol, prolactin, and ACTH. This selectivity makes ipamorelin the preferred GHS for combination with GHRH analogs (particularly CJC-1295), as the two agents act synergistically, GHRH increasing somatotroph responsiveness while GHS-R1a activation suppresses somatostatin release, producing GH pulse amplitudes substantially greater than either agent alone [30-32].

GHRP-2 and GHRP-6 are first-generation GHSs with greater GH pulse magnitude than ipamorelin but accompanied by cortisol and prolactin co-stimulation and, in the case of GHRP-6, pronounced appetite stimulation through central ghrelin receptor activation. Hexarelin is the most potent synthetic GHS by GH pulse magnitude and uniquely binds CD36 scavenger receptors on cardiac tissue, conferring cardioprotective effects through attenuation of ischaemia-reperfusion injury demonstrated in animal models independent of GH elevation. However, tachyphylaxis with continuous hexarelin administration limits its clinical utility for long-term GH optimization protocols [30,33].

Tissue Repair and Regenerative Peptides

BPC-157

Body protection compound-157 (BPC-157) is a synthetic pentadecapeptide (15 amino acids; Gly-Glu-Pro-Pro-Pro-Gly-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val) derived from a naturally occurring protective protein in human gastric juice. BPC-157 exerts its tissue-protective effects through multiple converging mechanisms: upregulation of nitric oxide (NO) synthesis in endothelial cells promoting angiogenesis; activation of growth factor expression including VEGF, EGF, and FGFR2; and modulation of the FAK-paxillin pathway to accelerate fibroblast migration into wound beds. Preclinical studies across rodent models have demonstrated accelerated healing of tendons, ligaments, muscles, bone, peripheral nerves, and gastrointestinal mucosa, including reversal of NSAID-induced gastric lesions and inflammatory bowel pathology. A 2024 systematic review of 544 publications on BPC-157 in orthopaedic applications identified only one study meeting methodological criteria for clinical evidence inclusion, underscoring the critical gap between preclinical abundance and clinical validation that characterizes this compound. Regulatory status: BPC-157 received FDA Category 2 designation in 2023 for compounded formulations, effectively prohibiting its use in compounding pharmacies in the United States. Clinical trials investigating BPC-157 in gastrointestinal indications are ongoing in Croatia [34-37].

Thymosin Beta-4 (TB-500)

Thymosin beta-4 (Tβ4) is an endogenous 43-amino-acid peptide ubiquitously expressed in human tissues that serves as the principal intracellular G-actin sequestering protein, maintaining the critical pool of unpolymerized actin required for cell migration. TB-500, the term used in the compounding and research context, refers to a synthetic fragment or formulation of Tβ4. Its healing mechanisms include promotion of actin polymerization at wound edges to facilitate cell migration; upregulation of matrix metalloproteinases for extracellular matrix remodeling; angiogenic effect through Notch and HIF-1alpha pathways; and anti-inflammatory activity through suppression of NF-κB-mediated cytokine production. Cardiac regeneration has been a particular focus: Smart et al. demonstrated in Nature that systemic Tβ4 administration mobilized epicardial progenitor cells and promoted neovascularization in a murine myocardial infarction model. No completed Phase 3 human RCTs exist for TB-500 in any indication. Thymosin beta-4 was placed on the World Anti-Doping Agency (WADA) prohibited list in 2011 and remains there, which has influenced compounding access patterns [38-40].

GHK-Cu (Copper Tripeptide)

GHK-Cu (glycyl-L-histidyl-L-lysine:copper 2+) is a naturally occurring copper-binding tripeptide found in human plasma, saliva, and urine, with plasma concentrations declining from approximately 200 ng/mL at age 20 to below 80 ng/mL by age 60. Its biological effects are extensive and partially mediated through broad gene expression modulation: Pickart et al. demonstrated that GHK-Cu up-regulates or down-regulates over 4,000 human genes, including genes associated with wound healing, collagen synthesis, anti-inflammatory signaling, and antioxidant defence. In skin biology, GHK-Cu stimulates synthesis of collagen types I and III, elastin, fibronectin, and glycosaminoglycans, while activating matrix metalloproteinases and their inhibitors in a balanced manner to promote wound healing without pathological fibrosis. Hair follicle stimulation and neuroprotection through BDNF-like signaling represent emerging areas of GHK-Cu research. Topical GHK-Cu is FDA-approved for cosmetic use, and systemic administration is under investigation for lung fibrosis, where anti-fibrotic gene modulation effects are particularly relevant [41,42].

Immunomodulatory Peptides

Thymosin Alpha-1 (Zadaxin)

Thymosin alpha-1 (Tα1; thymalfasin) is a 28-amino-acid N-terminal fragment of prothymosin alpha, produced by the thymus gland and involved in the maturation of T-lymphocytes and the regulation of innate and adaptive immune responses. Its immunostimulatory mechanisms include activation of Toll-like receptors TLR-2 and TLR-9 on dendritic cells and macrophages, promoting Th1 polarization and cytotoxic T-lymphocyte activity; augmentation of natural killer cell function; and induction of interferon-alpha production. Thymosin alpha-1 (Zadaxin; SciClone Pharmaceuticals) is approved in over 35 countries, primarily for chronic hepatitis B and C, and as an immune adjuvant in certain Asian markets. During the COVID-19 pandemic, retrospective and prospective studies from Italy and China demonstrated that thymosin alpha-1 administration in critically ill COVID-19 patients was associated with reduced mortality and restoration of lymphocyte counts. A systematic review by Shi et al. confirmed a statistically significant survival benefit in thymosin alpha-1-treated sepsis patients across multiple randomized trials (OR for survival 0.49; 95% CI 0.31–0.75) [43-46].

LL-37 (Cathelicidin)

LL-37 is a 37-amino-acid cationic amphipathic alpha-helical peptide derived from hCAP-18 (human cationic antimicrobial protein-18), the sole member of the cathelicidin family in humans. It is the primary endogenous antimicrobial peptide in skin, respiratory epithelium, and immune cells. LL-37 exerts direct microbicidal activity by inserting into and disrupting anionic bacterial membranes, demonstrating broad-spectrum efficacy against Gram-positive and Gram-negative bacteria, mycobacteria, fungi, and enveloped viruses including SARS-CoV-2 and influenza A. At sub-bactericidal concentrations, LL-37 exhibits immunomodulatory activity: it promotes keratinocyte migration and proliferation, stimulates angiogenesis via purinergic receptor activation, and modulates inflammatory cytokine production through multiple receptor-mediated pathways including FPR2/ALX. The vitamin D-LL-37 axis is clinically significant: vitamin D3 directly induces transcription of the cathelicidin antimicrobial peptide gene (CAMP), linking sunlight exposure and vitamin D status to innate antimicrobial defence. Clinical development of LL-37-based analogs is active, with AMPs and modified cathelicidin fragments in Phase 1 and Phase 2 evaluation for wound healing, antibiotic-resistant infections, and inflammatory dermatoses [47,48].

Cibinetide (ARA 290)

Cibinetide (ARA 290) is an 11-amino-acid peptide designed to selectively engage the innate repair receptor (IRR) , a heteromeric complex of the erythropoietin receptor (EPOR) and the common beta receptor (βcR), without activating erythropoietic signaling through the classical EPOR homodimer. This tissue-protective receptor pathway mediates cytoprotection, anti-inflammatory effects, and peripheral nerve repair in response to cellular stress signals. Phase 2 data from the IRACC trial in sarcoidosis-associated small fibre neuropathy demonstrated statistically significant improvements in corneal nerve fibre density, neuropathic pain scores, and metabolic parameters versus placebo, supporting further clinical development [49].

Neuroprotective and Cognitive-Enhancing Peptides

Semax

Semax (Met-Glu-His-Phe-Pro-Gly-Pro) is a synthetic heptapeptide analog of the ACTH(4-7) sequence, the minimal bioactive fragment of adrenocorticotropic hormone, modified with a C-terminal Pro-Gly-Pro extension to improve proteolytic stability. Despite its structural derivation from ACTH, Semax does not activate the HPA axis and exerts no glucocorticoid-stimulating effect. Instead, its principal mechanism of action involves upregulation of brain-derived neurotrophic factor (BDNF) expression in the hippocampus (1.4-fold increase in rat models), activation of nerve growth factor (NGF) signaling, and facilitation of dopaminergic and serotonergic neurotransmission. Semax has been registered in Russia since 1996 for acute ischaemic stroke, transient ischaemic attacks, and cognitive disorders. Clinical evidence from Russian randomized trials supports improved neurological outcome scores and faster functional recovery following ischaemic stroke. Intranasal administration provides effective CNS delivery; the peptide reaches cerebrospinal fluid within 30 minutes of intranasal dosing at clinically relevant concentrations [50,51].

Selank

Selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) is a synthetic heptapeptide analog of the endogenous tetrapeptide tuftsin (Thr-Lys-Pro-Arg), with a C-terminal Pro-Gly-Pro sequence that enhances metabolic stability. Selank’s primary pharmacological profile is anxiolytic, mediated through multiple mechanisms: enhancement of GABAergic transmission without direct benzodiazepine receptor binding (and therefore without tolerance, dependence, or sedation); modulation of serotonergic and dopaminergic tone; and suppression of inflammatory cytokines including IL-6. Like Semax, Selank upregulates BDNF in hippocampal tissue, contributing to anxiolytic effects through neuroplasticity enhancement. Selank has been registered in Russia since 2009 for the treatment of generalized anxiety disorder and neurasthenia. No large-scale Western randomized clinical trials have been completed [52,53].

Cerluten and Khavinson Bioregulators

Cerluten is a member of the Khavinson class of short di-to-tetrapeptide bioregulators developed at the St. Petersburg Institute of Bioregulation and Gerontology. These peptides are proposed to exert tissue-specific epigenetic regulation by penetrating cell membranes and interacting with DNA-histone complexes in a sequence-specific manner, modulating gene expression in targeted tissues. Cerluten specifically targets central nervous system tissue and is proposed to normalize neuronal gene expression patterns associated with age-related cognitive decline. Evidence comes primarily from Russian clinical and observational studies demonstrating improved cognitive performance metrics and quality of life in older patients. The mechanistic framework of short-peptide gene regulation remains an area of active research; independent validation in Western peer-reviewed controlled trial settings is limited, which constrains evidence-tier classification [54].

Longevity and Anti-Aging Bioregulators

Hallmarks of Aging as Therapeutic Targets

Lopez-Otin et al. described nine hallmarks of aging, including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication that provide a conceptual framework for anti-aging therapeutic targeting. Peptide-based interventions are particularly suited to modulating several of these hallmarks simultaneously, given their ability to mimic endogenous signaling molecules that naturally regulate tissue homeostasis [55].

Epithalon (Epitalon)

Epithalon (Ala-Glu-Asp-Gly; AEDG) is a synthetic tetrapeptide developed by Vladimir Khavinson as a more bioavailable and stable analog of pineal gland extract (epithalamin), which was historically administered to modulate neuroendocrine ageing. The best-characterized molecular mechanism of Epithalon is activation of telomerase, the ribonucleoprotein enzyme that adds TTAGGG repeats to eroding chromosome ends in human somatic cells. Khavinson et al. demonstrated statistically significant telomere elongation in human fetal fibroblast and kidney cell cultures following Epithalon treatment. Additional effects include restoration of circadian melatonin secretion rhythmicity in aged rodents and humans, reduction of spontaneous tumour incidence in long-term rodent studies, and improvements in biomarkers of immune senescence. Human clinical evidence, while predominantly from Russian longitudinal cohorts without randomized controls, suggests associations between cyclical Epithalon administration (10-day courses, twice yearly) and improvements in biomarkers of ageing, visual function, and longevity over 25-year observation periods. The evidence base, while mechanistically compelling, has not been subjected to independent large-scale placebo-controlled evaluation in Western trial settings, limiting its evidence tier classification [56,57].

Elamipretide (SS-31)

Elamipretide (D-Arg-Dmt-Lys-Phe-NH2; formerly MTP-131 or Bendavia) is a synthetic tetrapeptide that selectively concentrates in the inner mitochondrial membrane through electrostatic interaction with the anionic phospholipid cardiolipin, which is essential for electron transport chain (ETC) organization and cristae architecture. Cardiolipin undergoes peroxidation under conditions of oxidative stress, disrupting ETC complex super assembly and reducing ATP synthesis efficiency. Elamipretide binds cardiolipin with high affinity, preventing its peroxidation, restoring cristae morphology, and improving Complex I–IV electron coupling efficiency, resulting in reduced reactive oxygen species (ROS) production and increased ATP output per molecule of substrate. In the PROGRESS Phase 2 trial, elamipretide administered subcutaneously for 16 weeks in patients with primary mitochondrial myopathy produced statistically significant improvements in six-minute walk distance and Patient Global Impression of Change scores versus placebo. Cardiac applications include heart failure with preserved ejection fraction (HFpEF), ischaemia-reperfusion injury, and age-related mitochondrial dysfunction, indications aligned with the fundamental role of mitochondrial insufficiency in cardiovascular ageing [58,59].

Peptide for Sexual Function: Bremelanotide (PT-141)

PT-141 (bremelanotide) is a cyclic heptapeptide melanocortin receptor agonist structurally derived from alpha-melanocyte-stimulating hormone (α-MSH), with selective binding affinity for melanocortin receptors MC3R and MC4R expressed in hypothalamic and limbic brain regions governing sexual arousal, motivation, and desire. Unlike phosphodiesterase-5 (PDE5) inhibitors, which exert their pro-erectile effects through peripheral vascular mechanisms in the penile vasculature, bremelanotide acts centrally on the hypothalamic-limbic sexual arousal circuit, making it effective regardless of peripheral vascular status and applicable to both male and female sexual dysfunction. The RECONNECT clinical program evaluated bremelanotide in hypoactive sexual desire disorder (HSDD) in premenopausal women across two pivotal Phase 3 trials (RECONNECT Study A and Study B). Both studies demonstrated statistically significant improvements in the number of satisfying sexual events and reduction in distress related to low sexual desire versus placebo. Based on this evidence, the FDA approved bremelanotide (Vyleesi; AMAG Pharmaceuticals) in June 2019 for HSDD in premenopausal women, representing the second FDA-approved pharmacotherapy for female sexual dysfunction. Bremelanotide is administered subcutaneously 45 minutes prior to anticipated sexual activity and has a duration of action of approximately eight hours. The most common adverse effects are nausea (occurring in approximately 40% of subjects), flushing, and transient hypertension, which limit its use in patients with cardiovascular disease [60-62].

Regulatory Landscape and Safety Considerations

FDA-Approved Therapeutic Peptides

The FDA-approved therapeutic peptide landscape spans diverse indications: insulin analogs (diabetes), GLP-1 receptor agonists (diabetes and obesity), calcitonin (osteoporosis), parathyroid hormone analogs (osteoporosis), gonadotropin-releasing hormone analogs (oncology and reproductive medicine), tesamorelin (HIV lipodystrophy), bremelanotide (HSDD), and multiple antimicrobial peptides. The approval trajectory for GLP-1 receptor agonists has been particularly rapid, with semaglutide receiving FDA approval for cardiovascular risk reduction in non-diabetic patients with obesity (SELECT indication) and oral semaglutide (Rybelsus) representing the first oral GLP-1 receptor agonist for type 2 diabetes [1,18,63].

Compounding Regulatory Status (United States)

A critical regulatory development affecting the clinical use of investigational peptides in the United States was the FDA’s 2023 designation of over a dozen commonly prescribed peptides as Category 2 substances under the 503A bulk compounding framework, effectively prohibiting their preparation by compounding pharmacies. Peptides affected included CJC-1295, ipamorelin, BPC-157, thymosin alpha-1, thymosin beta-4, AOD-9604, PT-141, GHK-Cu, and others. The FDA cited insufficient human clinical safety data and significant immunogenicity concerns as rationale for this action. Following legal challenges from compounding pharmacy and clinical groups, a partial settlement in September 2024 led the FDA to submit key peptides for evaluation by the Pharmacy Compounding Advisory Committee (PCAC), with public meetings scheduled in 2024–2026 to evaluate peptides including CJC-1295, thymosin alpha-1, ipamorelin, and AOD-9604 for potential reclassification to Category 1 (permissible for compounding). As of June 2026, the FDA Pharmacy Compounding Advisory Committee meeting scheduled for July 23–24, 2026 will evaluate seven additional peptides for specific indications including ulcerative colitis, wound healing, obesity, and opioid withdrawal, potentially restoring compounding access for some agents [4,64,65].

Global Regulatory Variability

The global regulatory landscape for therapeutic peptides is characterised by marked heterogeneity. Thymosin alpha-1 (Zadaxin) holds approved drug status in China, Italy, and over 35 countries for viral hepatitis and immune augmentation, while remaining in an investigational or unapproved status in the United States. Semax and Selank are registered pharmaceuticals in Russia for neurological indications and are manufactured under GMP conditions there, but are not approved by the FDA, EMA, or TGA, placing them in a regulatory grey zone in Western countries. Clinicians operating in jurisdictions outside the United States should consult national regulatory frameworks, as prescribing access varies substantially. Patients accessing peptides through international compounding or research chemical suppliers face variable quality control and lack regulatory oversight [43,44,50,52,64].

General Safety Considerations

Therapeutic peptides as a class generally demonstrate favorable safety profiles relative to small-molecule drugs of comparable potency, owing to their metabolism into naturally occurring amino acids, absence of cytochrome P450-mediated drug-drug interactions, and receptor selectivity limiting off-target effects. Class-specific safety considerations include: GLP-1 receptor agonists, gastrointestinal adverse effects (nausea, vomiting, diarrhoea), rare pancreatitis, potential thyroid C-cell signal identified in rodents (not confirmed in human epidemiology), and gallbladder disease; GHRH analogs and GHSs causes fluid retention (oedema), carpal tunnel syndrome, insulin resistance elevation at supraphysiological IGF-1 levels, and potential risk of promoting growth in occult malignancy (theoretical, not confirmed in short-term trials); Bremelanotide causes nausea, transient hypertension, hyperpigmentation with repeated use; Tissue repair peptides (BPC-157, TB-500) are limited human safety data; immunogenicity risk with synthetic non-endogenous sequences cannot be excluded [2,3,17,20,27,32,36,40,61].

Future Directions and Research Frontiers

The therapeutic peptide field is entering an era of unprecedented pharmacological sophistication and clinical breadth. Several convergent trends are likely to define the next decade of peptide therapeutics in longevity and preventive medicine [1,2].

Multi-receptor Agonism and Polypharmacology

The clinical superiority of tirzepatide over GLP-1 monotherapy, and the Phase 2 results of retatrutide’s triple agonism, establish proof-of-concept that rationally designed multi-receptor peptides can achieve metabolic outcomes surpassing any single-target agent. The next generation of metabolic peptides in development includes combinations of GLP-1/amylin co-agonists (CagriSema), oxyntomodulin-derived triple agonists, and novel fibroblast growth factor 21 (FGF21) fusion peptides targeting hepatic lipid metabolism [24,25].

Oral Peptide Delivery

The approval of oral semaglutide (Rybelsus), using SNAC (sodium N-(8-[2-hydroxybenzoyl]amino)caprylate) as a permeation enhancer, established proof-of-concept for oral peptide bioavailability in a previously injectable-only drug class. Oral tirzepatide is now in Phase 3 evaluation, and oral delivery systems for GH secretagogues and other classes are in earlier development. Alternative delivery strategies including transdermal peptide patches, intranasal absorption (already exploited for Semax and Selank), sublingual formulations, and nanoparticle encapsulation are expanding the therapeutic peptide administration landscape and may substantially improve patient adherence [3,63].

Longevity Medicine and Biomarker-Guided Therapy

As the field of longevity medicine matures from theoretical geroscience to clinical practice, therapeutic peptides targeting specific aging hallmarks like telomere attrition (Epithalon), mitochondrial dysfunction (Elamipretide), immune senescence (thymosin alpha-1), and tissue homeostasis (GHK-Cu will require validated biomarker endpoints for efficacy assessment. Emerging biomarkers including epigenetic age clocks (GrimAge, PhenoAge), telomere length by PCR, mitochondrial DNA copy number, and circulating senescence-associated secretory phenotype (SASP) markers may enable patient stratification and objective treatment response measurement in future peptide longevity trials [55,56].

Artificial Intelligence in Peptide Design

Machine learning and artificial intelligence platforms, including protein structure prediction tools such as AlphaFold and generative molecular design algorithms are accelerating the discovery of novel therapeutic peptide sequences with optimized receptor affinity, selectivity, and metabolic stability. De novo AI-designed peptides with activities including antimicrobial, anticancer, and receptor-modulating properties have entered preclinical validation at a pace impossible with traditional discovery methods, promising a substantial expansion of the therapeutic peptide pipeline in the coming decade [66].

Conclusion

Therapeutic peptides represent a pharmacologically diverse and clinically productive class of agents that occupy a unique and rapidly expanding role in modern medicine. The differential evidence tiers across peptide categories, from the robust Phase 3 trial base of GLP-1 receptor agonists to the predominantly preclinical evidence supporting regenerative peptides, reflect both the maturity of research investment and the regulatory access each class has enjoyed [1,2].

For clinicians in longevity and preventive medicine, the practical implications are clear: GLP-1 receptor agonists and multi-receptor agonists represent evidence-based first-line pharmacotherapeutic options for metabolic disease, obesity, and cardiovascular risk reduction with a trial evidence base that rivals any drug class in modern medicine. Growth hormone secretagogues, particularly the CJC-1295/ipamorelin combination offer a physiologically rational approach to somatopause with a favorable safety profile, though adequately powered randomized trials in healthy ageing adults remain conspicuously absent. Tissue repair peptides occupy an important niche in sports medicine and gastroenterology, but their translation from animal model to human trial is urgently needed to establish evidence-based clinical protocols [7,17,18,20,31,35,36].

Regulatory fragmentation, between FDA-approved agents, internationally approved compounds, compounding-accessible peptides, and unregulated research chemicals represents the most significant practical barrier to rational peptide therapeutics. Standardized international clinical trial frameworks, transparent open-access trial registrations, and collaborative regulatory harmonization will be essential to realize the full therapeutic potential of this drug class. As the science of longevity medicine advances from epidemiological observation toward mechanistic intervention, therapeutic peptides, targeting the molecular hallmarks of ageing with a precision impossible for small molecules are positioned to become foundational tools in the preventive medicine armamentarium [55,64,65].

Reference

1. Muttenthaler M, King GF, Adams DJ, Alewood PF. Trends in peptide drug discovery. Nat Rev Drug Discov. 2021;20(4):309-325.

2. Lau JL, Dunn MK. Therapeutic peptides: Historical perspectives, current development trends, and future directions. Bioorg Med Chem. 2018;26(10):2700-2707.

3. Fosgerau K, Hoffmann T. Peptide therapeutics: current status and future directions. Drug Discov Today. 2015;20(1):122-128.

4. Craik DJ, Fairlie DP, Liras S, Price D. The future of peptide-based drugs. Chem Biol Drug Des. 2013;81(1):136-147.

5. Vlieghe P, Lisowski V, Martinez J, Khrestchatisky M. Synthetic therapeutic peptides: science and market. Drug Discov Today. 2010;15(1-2):40-56.

6. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3(3):153-165.

7. Teichman SL, Neale A, Lawrence B, Gagnon C, Castaigne JP, Frohman LA. Prolonged stimulation of growth hormone (GH) and insulin-like growth factor I secretion by CJC-1295, a long-acting analog of GH-releasing hormone, in healthy adults. J Clin Endocrinol Metab. 2006;91(3):799-805.

8. Nauck MA, Quast DR, Wefers J, Meier JJ. GLP-1 receptor agonists in the treatment of type 2 diabetes — state-of-the-art. Mol Metab. 2021;46:101102.

9. World Health Organization. Obesity and overweight. Fact Sheet. Geneva: WHO; 2024.

10. Nandakumar DN, Maiya AG, Shastry BA. Peptide therapeutics in age-related disorders: A review. Curr Protein Pept Sci. 2022;23(3):148-162.

11. Hauser AS, Attwood MM, Rask-Andersen M, Schiöth HB, Gloriam DE. Trends in GPCR drug discovery: new agents, targets and indications. Nat Rev Drug Discov. 2017;16(12):829-842.

12. De Graaf C, Donnelly D, Wootten D, et al. Glucagon-like peptide-1 and its class B G protein-coupled receptors: a long march to therapeutic successes. Pharmacol Rev. 2016;68(4):954-1013.

13. Müller EE, Locatelli V, Cocchi D. Neuroendocrine control of growth hormone secretion. Physiol Rev. 1999;79(2):511-607.

14. Veldhuis JD, Bowers CY. Human GH pulsatility: an ensemble property regulated by age and gender. J Endocrinol Invest. 2003;26(9):799-813.

15. Finan B, Yang B, Ottaway N, et al. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat Med. 2015;21(1):27-36.

16. Frias JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385(6):503-515. [SURPASS-2]

17. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989-1002. [STEP 1]

18. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389(24):2221-2232. [SELECT]

19. Athauda D, Maclagan K, Skene SS, et al. Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390(10103):1664-1675.

20. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205-216. [SURMOUNT-1]

21. Wadden TA, Chao A, Wadden TA. Tirzepatide versus semaglutide in adults with obesity. N Engl J Med. 2025;392:869-880. [SURMOUNT-5]

22. Pi-Sunyer X, Astrup A, Fujioka K, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med. 2015;373(1):11-22. [SCALE]

23. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322. [LEADER]

24. Jastreboff AM, Kaplan LM, Frías JP, et al. Triple hormone receptor agonist retatrutide for obesity. N Engl J Med. 2023;389(6):514-526.

25. Lau DCW, Bhatt DL, Heber MF, et al. Efficacy and safety of CagriSema in adults with obesity. N Engl J Med. 2025;392:321-334. [REDEFINE 1]

26. Heffernan M, Summers RJ, Thorburn A, et al. The effects of human GH and its lipolytic fragment (AOD9604) on lipid metabolism following chronic treatment in obese mice and beta(3)-AR knockout mice. Endocrinology. 2001;142(12):5182-5189.

27. Corpas E, Harman SM, Blackman MR. Human growth hormone and human aging. Endocr Rev. 1993;14(1):20-39.

28. Walker RF. Sermorelin: a better approach to management of adult-onset growth hormone insufficiency? Clin Interv Aging. 2006;1(4):307-308.

29. Falutz J, Allas S, Blot K, et al. Metabolic effects of a growth hormone-releasing factor in patients with HIV. N Engl J Med. 2007;357(23):2359-2370.

30. Bowers CY. Growth hormone-releasing peptides: history and mechanism of action. In: Growth Hormone Secretagogues. Academic Press; 1996. p. 9-28.

31. Raun K, Hansen BS, Johansen NL, et al. Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol. 1998;139(5):552-561.

32. Popovic V, Leal A, Micic D, et al. GH-releasing hormone and GH-releasing peptide-6 for diagnostic testing in GH-deficient adults. Lancet. 2000;356(9236):1137-1142.

33. Torsello A, Bresciani E, Rossoni G, et al. Hexarelin protects against the cardiotoxic effects of doxorubicin in the rat. J Endocrinol. 2003;177(2):371-379.

34. Sikiric P, Seiwerth S, Rucman R, et al. Toxicity by NSAIDs: counteraction by stable gastric pentadecapeptide BPC 157. Curr Pharm Des. 2013;19(1):76-83.

35. Sikiric P, Seiwerth S, Rucman R, et al. Stable gastric pentadecapeptide BPC 157: novel therapy in gastrointestinal tract. Curr Pharm Des. 2011;17(16):1612-1632.

36. Vasireddi AK, Saini K, Garg A, et al. Is BPC-157 ready for clinical use? A systematic review. J Orthop Res. 2024;42(5):1023-1036.

37. U.S. Food and Drug Administration. Bulk drug substances nominated for use in compounding under section 503A. FDA; 2023.

38. Goldstein AL, Hannappel E, Kleinman HK. Thymosin beta4: actin-sequestering protein moonlights to repair injured tissues. Trends Mol Med. 2005;11(9):421-429.

39. Smart N, Risebro CA, Melville AA, et al. Thymosin beta-4 induces adult epicardial progenitor mobilization and neovascularization. Nature. 2007;445(7124):177-182.

40. World Anti-Doping Agency. Prohibited List 2024. Montreal: WADA; 2024.

41. Pickart L, Vasquez-Soltero JM, Margolina A. GHK-Cu may prevent oxidative stress in skin by regulating copper and modifying expression of numerous antioxidant genes. Cosmetics. 2015;2(2):236-247.

42. Pickart L, Margolina A. Regenerative and protective actions of the GHK-Cu peptide in the light of the new gene data. Int J Mol Sci. 2018;19(7):1987.

43. Goldstein AL, Goldstein AL. From lab to bedside: emerging clinical applications of thymosin alpha 1. Expert Opin Biol Ther. 2009;9(5):593-608.

44. Camerini R, Garaci E. Historical review of thymosin alpha 1 in infectious diseases. Expert Opin Biol Ther. 2015;15(Suppl 1):S117-127.

45. Shi C, Shi Q, Zhu L, et al. Thymosin α1 for improvement of survival in sepsis. Crit Care. 2021;25(1):181.

46. Liu F, Xu A, Han B, et al. Thymosin alpha1 in COVID-19 critically ill patients. Clin Immunol. 2020;219:108516.

47. Zanetti M. Cathelicidins, multifunctional peptides of the innate immunity. J Leukoc Biol. 2004;75(1):39-48.

48. Bin Hafeez A, Jiang X, Bergen PJ, Zhu Y. Antimicrobial peptides: an update on classifications and databases. Int J Mol Sci. 2021;22(21):11691.

49. Brines M, Dunne AN, van Velzen M, et al. ARA 290, a nonerythropoietic peptide engineered from the erythropoietin helix B surface, improves metabolic control and neuropathic symptoms in patients with type 2 diabetes. Mol Med. 2014;20:658-666.

50. Semax. Pharmacological properties, clinical use. Moscow: Peptogen; 2018.

51. Gusev EI, Skvortsova VI, Dambinova SA, et al. Neuroprotective effects of Semax in acute period of hemispheric ischemic stroke. Cerebrovasc Dis. 1997;7(3):162-166.

52. Boyko SS, Zolotov NN, Shevchenko VP, et al. Pharmacokinetics of selank after intranasal administration. Exp Oncol. 2008;30(1):77-80.

53. Uchakina ON, Uchakin PN, Mabry TR, et al. Immunomodulatory effects of selank in patients with anxiety-asthenic disorders. Zh Nevrol Psikhiatr Im S S Korsakova. 2008;108(5):71-75.

54. Khavinson VKh. Tissue-specific effects of peptide bioregulators. Neuroendocrinol Lett. 2002;23(Suppl 3):21-41.

55. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194-1217.

56. Khavinson VK, Bondarev IE, Butyugov AA. Epithalon peptide induces telomerase activity and telomere elongation in human somatic cells. Bull Exp Biol Med. 2003;135(6):590-592.

57. Anisimov VN, Khavinson VKh, Popovich IG, et al. Effect of Epitalon on biomarkers of aging, life span and spontaneous tumor incidence in female Swiss-derived SHR mice. Biogerontology. 2003;4(4):193-202.

58. Szeto HH. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. Br J Pharmacol. 2014;171(8):2029-2050.

59. Karaa A, Bertrand Haas R, et al. Randomized dose-escalation trial of elamipretide in adults with primary mitochondrial myopathy. Neurology. 2018;90(14):e1212-1221. [MMTT]

60. Molinoff PB, Shadiack AM, Earle D, Diamond LE, Quon CY. PT-141: a melanocortin agonist for the treatment of sexual dysfunction. Ann N Y Acad Sci. 2003;994:96-102.

61. Clayton AH, Althof SE, Kingsberg S, et al. Bremelanotide for female sexual dysfunctions in premenopausal women. Obstet Gynecol. 2016;128(6):1241-1250. [RECONNECT]

62. U.S. Food and Drug Administration. FDA approves new treatment for hypoactive sexual desire disorder in premenopausal women [Press release]. Silver Spring: FDA; 2019.

63. Hamman JH, Enslin GM, Kotze AF. Oral delivery of peptide drugs: barriers and developments. BioDrugs. 2005;19(3):165-177.

64. Regulatory Status of Peptide Compounding in 2025. Washington DC: Frier Levitt; 2025. Available from: https://www.frierlevitt.com/articles/regulatory-status-of-peptide-compounding-in-2025/

65. U.S. Food and Drug Administration. Pharmacy Compounding Advisory Committee: Bulk Drug Substances Review. Silver Spring: FDA; 2026.

66. Ferruz N, Heinzinger M, Akdel M, et al. From sequence to function through structure: deep learning for protein design. Comput Struct Biotechnol J. 2022;20:1777-1794.