Protease inhibitors targeting the main protease and papain-like protease of coronaviruses

ABSTRACT

Introduction

The two cysteine proteases from the coronaviruses, which produced deadly outbreaks in the last two decades, SARS CoV-1/2, and MERS, the main protease (M^pro) and the papain-like protease (PLP) are conserved among the three pathogens and started to be considered as exciting drug targets for developing antivirals.

Areas covered

We review the drug design landscape in the scientific and patent literature to design peptidomimetic and non-peptidomimetic protease inhibitors (PIs) targeting these proteins.

Expert opinion

The X-ray crystal structures of some of these proteases, alone and in complex with various inhibitors, were crucial for the discovery of effective such compounds, some of which also showed considerable antiviral activity and are considered preclinical candidates to fight these emerging infections, which in the case of Covid-19 already provoked an unprecedented worldwide pandemic.

KEYWORDS:

• Coronavirus
• SARS-CoV-1/2
• MERS
• main protease
• papain-like protease
• inhibitor

Article highlights

∙ SARS, MERS, and Covid-19 triggered when a virus passed from animals to humans, giving rise to a zoonosis which started to spread worldwide.

∙ SARS-CoV, MERS-CoV and SARS-CoV-2 bind to a cellular membrane receptor and invade the host cell, coopting some of its components to make many copies of themselves.

∙ CoV genome encodes for structural proteins and non-structural proteins (Nsp), with nucleotide organization typical of β coronaviruses.

∙ Targeting of two non-structural proteins Nsp3 and Nsp5 of CoV, the two proteases PLP and M^pro, respectively, received major attention as an approach for inhibiting virus replication.

∙ PLP and M^pro are cysteine proteases: M^pro is a homodimer with a Cys-His dyad at the active site; PLP is a monomer with a Cys-His-Asp canonical catalytic triad.

∙ There are two main approaches for designing M^pro inhibitors, the peptidomimetic and the non-peptidomimetic approach, which have been used for obtaining protease inhibitors (PIs) for other viral (and non-viral) proteases.

∙ Using peptidomimetic inhibitors of M^pro from SARS-CoV1 and MERS several highly effective SARS-CoV-2 M^pro inhibitors were designed.

∙ They incorporate Michael acceptors, of the aldehyde, thioketone, α-ketoamides, trans-α,β-unsaturated alkyl/benzyl esters, chloromethyl ketones, hydroxymethyl ketones type or are disulfides/dithiocarbamtes which react with the catalytic triad cysteine.

∙ Small molecule inhibitors belonging to a variety of classes were reported for the PLP proteases from the three coronaviruses discussed.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.