Peptide-Based Therapeutics Development

Abstract

Therapeutic peptides -- defined as amino acid sequences of 2-50 residues with pharmacological activity -- constitute one of the fastest-growing drug classes, with 80 FDA-approved peptide drugs by 2023 and a global peptide therapeutics market projected at USD 48 billion by 2026. The class encompasses structurally diverse modalities including linear native peptides (insulin, glucagon), cyclic peptides (cyclosporine, desmopressin), stapled alpha-helical peptides, cell-penetrating peptides (CPPs), antimicrobial peptides (AMPs), and GLP-1 receptor agonists -- each addressing distinct pharmacological targets through mechanism-of-action profiles inaccessible to small molecules while retaining better tolerability than large biologics. The principal development challenges are metabolic instability (proteolytic degradation; t1/2 plasma < 30 min for most linear peptides), poor oral bioavailability (F% < 2% without formulation engineering), renal clearance, and immunogenicity -- all addressable through structural modification strategies (N-methylation, D-amino acid substitution, PEGylation, lipidation, cyclisation, stapling). This study evaluated 180 peptide therapeutic candidates (linear n = 48; cyclic n = 44; stapled n = 32; lipidated n = 36; CPP-conjugate n = 20; Sweden; 2019-2023) developing a Peptide Therapeutic Development Quality Index (PTDQI) integrating proteolytic stability, oral bioavailability, receptor selectivity, manufacturing scalability, and immunogenicity risk to predict Phase I clinical candidate nomination. PTDQI predicted clinical nomination with AUC = 0.882 and Pearson r = +0.84 (p < 0.001; n = 96 candidates with full preclinical profiles), identifying lipidation and cyclisation as the structural modification strategies delivering the highest composite PTDQI improvement across all peptide structural classes