Since the first medical use of insulin to treat type 1 diabetes in 1922, the field of peptide therapeutics has seen remarkable growth, with over 100 peptides approved by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA) (1). Technological discoveries and advances in solid-phase peptide synthesis, recombinant technologies, peptide phage display libraries, and more recently, AI-aided de novo protein design (2024 Chemistry Nobel Prize) have propelled the peptide field forward throughout the century (2). Parallel progress in medicinal chemistry, antibody and oligonucleotide therapeutics, and the novel payloads for antibody-drug conjugates (ADCs) have fueled the burgeoning field of peptide conjugates bearing multi-mode biological functions (Figure 1).
Peptide therapeutics often suffer from short half-lives due to rapid degradation and clearance. Conjugation with polymers such as polyethylene glycol (PEG) can significantly increase peptide half-life by shielding them from proteolytic degradation and reducing renal clearance (3).
Similarly, lipid conjugation can extend peptide half-life. FDA-approved Glucagon-like peptide-1 (GLP-1) based peptide analogue drugs such as Semaglutide, Liraglutide, and the dual GLP-1/GIP agonist Tirzepatide have fatty acid conjugated to the lysine sidechains, promoting albumin binding and extended half-life (4).
Discover how early analytical strategies enabled the structural characterization of human CGRP, a potent vasodilator. This foundational Nature paper offers valuable insights into peptide analysis techniques still relevant today.
Peptide-drug conjugates (PDCs) represent an emerging therapeutic modality where a drug payload is covalently conjugated via cleavable or non-cleavable linkers to target-specific peptides (5, 6). Inspired by ADCs, PDCs offer several advantages over ADCs:
Two radioligand-conjugated PDCs, Lutathera and Pluvicto, are already on the market. A diverse pipeline of peptide and payload combinations is currently being evaluated in clinical trials for cancer treatment (5), as well as pre-clinically for anti-viral, anti-bacterial, neurodegenerative, and anti-inflammatory applications (6).
Oligonucleotides such as small interfering RNA (siRNA) and antisense oligonucleotides (ASOs) are a highly promising therapeutics class, with 20 drugs approved to date by the FDA and EMA. To address their intrinsic drawbacks such as lack of targeting specificity, limited membrane permeability, and poor endosomal escape, oligonucleotide conjugation to other molecules is being actively explored.
Antibody-peptide conjugates are an expanding class of therapeutics where the antibody provides targeting and half-life extension functions to the peptide. This modality is highly relevant to chemically modified peptides, not amenable to classic antibody-peptide genetic fusion approaches.
The structural complexity of peptide conjugates requires a suite of advanced analytical tools since each conjugation strategy brings its own challenges, but with the right techniques, these can be effectively addressed.
Mass spectrometry-based intact mass analysis is the typical method performed on a conjugate to assess general composition, payload number, and any process-related impurities present in the sample.
To confirm the amino acid sequence and the conjugation points, a combination of analytical techniques is employed:
Conjugation-induced changes in higher order structures such as α-helices and β-sheets can be analyzed using:
Conjugation of peptides to other moieties can cause aggregate formation, which can be assessed by:
Over the past century, peptide therapeutics have evolved from animal-derived insulin to a broad array of clinically significant peptides. Today, the conjugation of peptides to other drug modalities has led to the development of multi-mode therapeutics such as peptide-lipid, peptide-polymer, peptide-drug, peptide-oligonucleotide, and antibody-peptide conjugates. Each class of peptide bioconjugates presents unique analytical challenges, which can be addressed and analyzed across BioPharmaSpec’s global laboratories.
Whether you're navigating early-stage development or preparing for regulatory submission, BioPharmaSpec offers expert-driven peptide analysis services to help you meet structural characterization requirements with confidence.
Contact our scientists today to discuss your peptide project and receive a tailored analytical strategy.
