Noncovalent PEGylation of protein and peptide therapeutics

• Published in: Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology 2023-09, Vol.15 (5), p.e1897-e1897
• Main Author: Andrianov, Alexander K
• Format: Article
• Language: English
• Subjects: Biological activity; Conjugation; Control stability; Drug delivery; Drug delivery systems; Drug development; Drug discovery; Immunogenicity; In vivo methods and tests; Nanotechnology; Pharmacokinetics; Physiology; Polyethylene glycol; Production costs; Proteins; Supramolecular compounds; Technology
• ISSN: 1939-5116; 1939-0041
• DOI: 10.1002/wnan.1897

Clinical applications of protein therapeutics-an advanced generation of drugs characterized by high biological specificity-are rapidly expanding. However, their development is often impeded by unfavorable pharmacokinetic profiles and largely relies on the use of drug delivery systems to prolong their in vivo half-life and suppress undesirable immunogenicity. Although a commercially established PEGylation technology based on protein conjugation with poly(ethylene glycol) (PEG)-protective steric shield resolves some of the challenges, the search for alternatives continues. Noncovalent PEGylation, which mainly relies on multivalent (cooperative) interactions and high affinity (host-guest) complexes formed between protein and PEG offers a number of potential advantages. Among them are dynamic or reversible protection of the protein with minimal loss of biological activity, drastically lower manufacturing costs, "mix-and-match" formulations approaches, and expanded scope of PEGylation targets. While a great number of innovative chemical approaches have been proposed in recent years, the ability to effectively control the stability of noncovalently assembled protein-PEG complexes under physiological conditions presents a serious challenge for the commercial development of the technology. In an attempt to identify critical factors affecting pharmacological behavior of noncovalently linked complexes, this Review follows a hierarchical analysis of various experimental techniques and resulting supramolecular architectures. The importance of in vivo administration routes, degradation patterns of PEGylating agents, and a multitude of potential exchange reactions with constituents of physiological compartments are highlighted. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.