Delving into the Latest Updates on SARS-CoV-2 Mpro inhibitors(Universität zu Lübeck) with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Compound 6d(Universität zu Lübeck)

Target

SARS-CoV-2 Mpro

Action

inhibitors

Mechanism

SARS-CoV-2 Mpro inhibitors(SARS-CoV-2 main protease inhibitors)

Therapeutic Areas

Infectious Diseases

Active Indication

Coronavirus Infections

Inactive Indication-

Originator Organization

Universität zu Lübeck

Active Organization

Universität zu Lübeck

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

The main protease M^pro is a clinically validated target to treat infections by the coronavirus SARS-CoV-2. Among the first reported M^pro inhibitors was the peptidomimetic α-ketoamide 13b, whose cocrystal structure with M^pro paved the way for multiple lead-finding studies. We established structure-activity relationships for the 13b series by modifying residues at the P1', P3, and P4 sites. Guided by cocrystal structures, we reduced the P1' substituent size to better fill the pocket and added a fluorine substituent to the pyridone ring, enabling a new hydrogen bond with Gln189 in P3. Among 22 novel analogues, 6d and 12d inhibited M^pro with IC₅₀s of 110 nM and 40 nM, improving the potency of 13b by up to 9.5-fold. Compound 6d had pronounced antiviral activity with an EC₅₀ of 1.6 μM and was stable in plasma and microsomes. The study illustrates the potential of structure-based design to systematically improve peptidomimetic α-ketoamides.

100 Deals associated with SARS-CoV-2 Mpro inhibitors(Universität zu Lübeck)

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