Peptides as a platform for targeted therapeutics for cancer: peptide-drug conjugates (PDCs).

Bethany M. Cooper,Jessica Iegre,Daniel H. O' Donovan,Maria Ölwegård Halvarsson,David R. Spring

doi:10.1039/d0cs00556h

Abstract

Peptides can offer the versatility needed for a successful oncology drug discovery approach. Peptide-drug conjugates (PDCs) are an emerging targeted therapeutic that present increased tumour penetration and selectivity. Despite these advantages, there are still limitations for the use of peptides as therapeutics exemplified through their slow progression to get into the clinic and limited oral bioavailability. New approaches to address these problems have been studied and successfully implemented to enhance the stability of peptides and their constructs. There is great promise for the future of PDCs with two molecules already on the market and many variations currently undergoing clinical trials, such as bicycle-toxin conjugates and peptide-dendrimer conjugates. This review summarises the entire process needed for the design and successful development of an oncology PDC including chemical and nanomaterial strategies to enhance peptide stability within circulation, the function of each component of a PDC construct, and current examples in clinical trials.

Highlights

Europe and Japan markets, there are more than 100 peptide drugs used to treat a range of diseases.[2]
Close interpretation of the results found that orally available peptides had 5 times more H-bond donors and acceptors than what was considered as acceptable by Lipinski’s Rule of 5 (Ro5) for small molecules.[4]
Despite peptides being currently under-represented in clinical trials in comparison to small molecules and biologics, they provide exquisite versatility that can aid the design of targeted therapeutics

Summary

Introduction

Europe and Japan markets, there are more than 100 peptide drugs used to treat a range of diseases.[2]. Alternative to cleavable linkers are non-cleavable linkers These linkers are not activated through external stimuli such as a chemically induced one.[35] A non-cleavable linkers mechanism of action starts with the peptide/mAb being metabolised to leave the payload-linker construct, which can go on to escape out of the endosome/lysosome to kill the cell.[35] cleavable linkers are preferred to non-cleavable for the development of targeted therapeutics, they present increased stability in circulation. A bicycle peptide is typically between 9–20 amino acids long and has 3 cysteine residues within the sequence.[10] These cysteine residues react with a small molecule linker to constrain the peptide in a rigid conformation (Fig. 13).[46] The bicycles can be used as transporters for drug molecules through bicycletoxin conjugates (BTCs) These conjugates offer several advantages over ADCs which include deeper tumour penetration, rapid extravasation and slower renal clearance.[46] The drug is attached to the bicycle peptide ensuring the conformation is not hampered. Future work for this dendrimer conjugate includes testing on other colorectal cancer cell lines.[50]

Conclusions

Findings

Impact Story: Developing the Tools to Evaluate Complex Drug Products