Peptide-Based Inhibitors of ADAM and ADAMTS Metalloproteinases.

Stefano Pluda,Ylenia Mazzocato,Alessandro Angelini

doi:10.3389/fmolb.2021.703715

Abstract

ADAM and ADAMTS are two large metalloproteinase families involved in numerous physiological processes, such as shedding of cell-surface protein ectodomains and extra-cellular matrix remodelling. Aberrant expression or dysregulation of ADAMs and ADAMTSs activity has been linked to several pathologies including cancer, inflammatory, neurodegenerative and cardiovascular diseases. Inhibition of ADAM and ADAMTS metalloproteinases have been attempted using various small molecules and protein-based therapeutics, each with their advantages and disadvantages. While most of these molecular formats have already been described in detail elsewhere, this mini review focuses solely on peptide-based inhibitors, an emerging class of therapeutic molecules recently applied against some ADAM and ADAMTS members. We describe both linear and cyclic peptide-based inhibitors which have been developed using different approaches ranging from traditional medicinal chemistry and rational design strategies to novel combinatorial peptide-display technologies.

Highlights

The “A-disintegrin and metalloproteinase” (ADAM) and “A-disintegrin and metalloproteinase with thrombospondin motifs” (ADAMTS) are closely related matrix zinc-dependent metalloproteinases that belong to the adamlysin protein family (Takeda, 2016)
ADAM and ADAMTS proteins have a peripheral extracellular localisation, which makes them ideal targets of peptide-based drugs
The majority of linear and cyclic peptide inhibitors described in this mini review were developed using traditional medicinal chemistry approaches and structure–activity relationship studies on natural substrates and/or endogenous inhibitors

Summary

Introduction

The “A-disintegrin and metalloproteinase” (ADAM) and “A-disintegrin and metalloproteinase with thrombospondin motifs” (ADAMTS) are closely related matrix zinc-dependent metalloproteinases that belong to the adamlysin protein family (Takeda, 2016). There is a great interest in developing novel ADAM and ADAMTS inhibitors that can selectively target a single member of each family. Most protein-based inhibitors do not bind the active site of the ADAM and ADAMTS enzymes but recognise surface-exposed loops that are poorly conserved between closely related family members.

Results

Conclusion