Integrative Biomedical Research
Integrative Biomedical Research (Journal of Angiotherapy) | Online ISSN 3068-6326
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Volume 10 Number 2 2026
REVIEWS (Open Access)
Peptide and Macrocycle Chemistry in the Development of Metabolic and Obesity Therapeutics
Sau Har Lee1,2, Yong Hui Wong1, Saif al deen M. Khatlan 3*
Integrative Biomedical Research 10 (2) 1-22 https://doi.org/10.25163/biomedical.10210960
Submitted: 03 September 2026 Revised: 25 October 2026 Accepted: 04 November 2026 Published: 06 November 2026
Abstract
For most of the past half-century obesity resisted pharmacology, and the reasons were chemical as much as physiological. Small molecules are inexpensive, oral and membrane-permeant, yet their modest contact surfaces cannot grip the extended, shallow interfaces of class B G-protein-coupled receptors. Monoclonal antibodies engage those targets faithfully but stay confined to the extracellular compartment and to costly parenteral manufacture. Peptides and macrocycles of roughly 500 to 3,000 Da occupy the ground between, and from this "Goldilocks" window the current generation of metabolic medicines has emerged. This review synthesises four converging strands of evidence. First, the structural chemistry that rescued peptides from their own fragility: position-2 substitution with alpha-aminoisobutyric acid, macrocyclisation, hydrocarbon stapling, backbone N-methylation and fatty diacid acylation, which converts a two-minute half-life into five to seven days via reversible albumin binding. Second, the pharmacological escalation from GLP-1 mono-agonism through dual and triple incretin agonism to amylin co-agonism, lifting mean weight loss from roughly 15% with semaglutide to 24% with retatrutide and amycretin, approaching though not yet matching bariatric benchmarks. Third, the delivery problem, where permeation enhancers, ingestible micro-injectors and non-peptide small-molecule agonists each solve part of a difficulty none solves completely. Fourth, manufacture, where a process mass intensity near 33,000 for early-phase synthetic peptides sits uncomfortably beside multi-tonne global demand and tightening solvent regulation. We argue, tentatively, that the next decisive gains will come from delivery and process chemistry rather than further receptor combinatorics, and that tolerability, not potency, now caps how much weight these drugs can remove.
Keywords: therapeutic peptides; macrocycles; GLP-1 receptor agonists; unimolecular poly-pharmacology; obesity; oral peptide delivery; green peptide synthesis
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