Strategic Approaches for Overcoming Peptide and Protein Drug Limitations

Protein and peptide drugs have become essential in treating numerous diseases due to their high specificity and therapeutic potential. However, their clinical application faces several challenges, including chemical instability, physical instability, short in vivo half-life, low oral bioavailability, and immunogenicity. These issues reduce drug efficacy and limit patient compliance. This review critically examines these limitations and presents current strategies to address them. PEGylation, the covalent or noncovalent attachment of polyethylene glycol (PEG) molecules to proteins, is highlighted for its ability to increase stability, reduce renal clearance, lower immunogenicity, and extend half-life. The review distinguishes between random and site-specific PEGylation, highlighting site-specific methods that preserve protein activity while optimizing pharmacokinetics. Additionally, the encapsulation of proteins in polymeric and lipid-based delivery systems is discussed to protect drugs from enzymatic degradation, control their release, and enhance absorption. Biobetter approaches, including site-directed mutagenesis, are also presented to improve protein stability and reduce immunogenicity. Market data and approved drug examples illustrate the impact of these strategies. Overall, the article provides a comprehensive overview of innovative pharmaceutical and biotechnological methods that enhance the clinical performance and market viability of protein therapeutics.