Methods for engineering therapeutic peptides

Peptides are a class of drugs that have become increasingly important and influential for the treatment of many human diseases. Compared to traditional small molecule drugs, peptides have the potential for higher target specificity and potency, along with better safety profiles. On the other hand, the complex and fragile nature of peptides poses significant challenges for their administration. Of particular concern is that they are often unstable and can be rapidly degraded by various proteases after dosing. To address these inherent problems of peptides, many different methods have been attempted. Here, we briefly review these methods, with an emphasis on the effect of each method.

Aggregation properties of a therapeutic peptide for rheumatoid arthritis:A spectroscopic and molecular dynamics study

The biological properties of therapeutic peptides,such as their pharmacokinetics and pharmacodynamics,are correlated with their structure and aggregation properties.Herein,we studied the aggregation properties of a therapeutic peptide(CIGB-814),currently in phase 2 clinical trial,for the treatment of rheumatoid arthritis over a wide range of concentrations(μM-mM).We applied spectroscopic techniques(fluorescence,circular dichro-ism,resonance,and dynamic light scattering),atomic force microscopy,and molecular dynamics simulations to determine the aggregation mechanism of CIGB-814.We found that the hierarchical aggregation of CIGB-814 at micromolar concentrations was initiated by the formation of peptide oligomers.Subsequently,the peptide oligomers trigger the nucleation and growth of peptide nanostructures(cac=123μM),ultimately leading to the fibrillization of CIGB-814(cac’=508μM).These results pave the way for a deeper understanding of the CIGB-814 therapeutic activity and may give important insights on its pharmacokinetics.

Exploiting Complex-Type N-Glycan to Improve the in Vivo Stability of Bioactive Peptides

Peptides can be potentmolecules with high efficacy and selectivity in the development of biotherapeutics.However,the poor pharmacokinetic properties of peptides pose major challenges for their broader medicinal applications.Inspired by the proteinstabilizing role of natural N-glycosylation,we design and synthesize a series of parathyroid hormone(PTH)peptides(1-34),bearing either N-GlcNAc or biantennary complex-type N-glycan modification,and evaluate their serum stability and biological activities.The results indicate that an N-Asn-linked complex-type sialylundecasaccharide can increase the serum half-life and in vivo bioactivity of PTH peptides with a broad tolerance of modification sites.Further,hydrogen/deuterium exchange mass spectroscopy indicates that the larger-sized Nglycan can induce enhanced hydration dynamics in its surroundings,which may facilitate an improved resistance for the peptide against enzymatic proteolysis.This sialylundecasaccharide-based peptideengineering strategy has also been applied to glucagon-like peptide-1(7-37),leading to glycopeptides with enhanced hypoglycemic activity and acting time in vivo.Together,these results demonstrate the potential of using sialylated complextype N-glycan as a general engineering strategy for developing long-acting peptide therapeutics.

Current development of bicyclic peptides

Bicyclic peptides,a class of polypeptides with two loops within their structure,have emerged as powerful tools in the development of new peptide drugs.They have the potential to bind to challenged drug targets,with antibody-like affinity and selectivity.Meanwhile,bicyclic peptides possess small molecule-like access to chemical synthesis,which is conducive to large-scale synthesis and screening.In the last five years,bicyclic peptide technology has been increasingly developed,and researchers have carried out a variety of studies to elucidate the potential functions of bicyclic peptides.With the continuous development of synthetic methods and the advances of new technology to build bicyclic peptide libraries,bicyclic peptides are now becoming widely used in the development of new drugs for various diseases.This perspective provides an overview of the structure types,synthesis and applications of bicyclic peptides in current drug development,and our own views on future challenges of bicyclic peptides.

Development of peptide inhibitors of HIV transmission

Treatment of HIV has long faced the challenge of high mutation rates leading to rapid development of resistance,with ongoing need to develop new methods to effectively fight the infection.Traditionally,early HIV medications were designed to inhibit RNA replication and protein production through small molecular drugs.Peptide based therapeutics are a versatile,promising field in HIV therapy,which continues to develop as we expand our understanding of key protein-protein interactions that occur in HIV replication and infection.This review begins with an introduction to HIV,followed by the biological basis of disease,current clinical management of the disease,therapeutics on the market,and finally potential avenues for improved drug development.