Peptide and Protein Bioconjugation: A Useful Tool to Improve the Biological Performance of Biotech Drugs.

In the last decades, much effort has been put toward understanding the biological machinery that rules the physiological activities of cells. An advanced knowledge of cell biology and of the biochemical mechanisms that underlie pathological conditions has allowed for the development of new, efficient drugs for target therapies. Molecular biology and biotechnology, in particular, have exerted a profound influence on drug discovery, opening new possibilities in the pharmaceutical exploitation of biotech molecules. Due to their high activities and biological specificities, protein drugs have received much attention from pharmaceutical companies. Several proteins, including hormones (e.g., insulin, growth hormone and erythropoietin), cytokines (e.g., α-TNF and IFN), antibodies or antibody fragments (e.g., infliximab, rituximab and cetuximab), enzymes (e.g., asparaginase and adenosine deaminase), vaccines and other biomodulators are currently available in the pharmaceutical market and many others are under investigation. In the next few years, biotech drugs are expected to represent over 35% of the products in the pharmaceutical company pipelines and the market is forecasted to grow rapidly. Despite their remarkable success, protein drugs continue to present important drawbacks related to their manipulation, storage and delivery. Proteins are highly structured and fragile macromolecules and the preservation of their structural conformations is paramount to their activities. Proteins can easily undergo physical, chemical and enzymatic denaturation, degradation and inactivation. Protein unfolding can be caused by temperature changes, desiccation or freeze-drying, shear forces, interactions with excipients and hydrophobic surfaces, contact with organic solvents, salting out and pH alterations. Chemical degradation may involve oxidation, disulfide exchange, deamidation and/or pH-dependent intra-chain cleavage. Enzymatic degradation results in the detachment of terminal amino acids or intrachain polypeptide fragmentation. Additional problems with the therapeutic exploitation of proteins are related to their poor bioavailability. The hydrophilic character of these macromolecules and their susceptibility to enzymatic degradation limit their absorption through biomembranes and promote their rapid elimination from the circulation. Finally, the intrinsic immunogenic character of these xenoproteins may be responsible for their inactivation and elimination. Therefore, the amelioration of the poor physicochemical and biopharmaceutical properties of proteins is a prerequisite to their therapeutic exploitation. Advances in genetic engineering and post-production derivatisation techniques, such as glycosylation, acylation and polymer conjugation, allow for the preparation of novel protein derivatives with enhanced or novel therapeutic applications. These new biotech drugs are rapidly being integrated into the pharmaceutical arsenal.