Delving into the Latest Updates on VEEV nsP2 inhibitors(The University of North Carolina at Chapel Hill) with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Compound 10(The University of North Carolina at Chapel Hill)

Target

VEEV nsP2

Action

inhibitors

Mechanism

VEEV nsP2 inhibitors(VEEV non-structural protein 2 inhibitors)

Therapeutic Areas

Infectious Diseases

Active Indication

Alphavirus Infections

Inactive Indication-

Originator Organization

The University of North Carolina at Chapel Hill

Active Organization

The University of North Carolina at Chapel Hill

Inactive Organization-

License Organization-

Drug Highest PhaseDiscovery

First Approval Date-

Regulation-

Author: Moorman, Nathaniel J. ; Nandakumar, Meganathan ; Heise, Mark T. ; Merten, Eric M. ; Sears, John D. ; Hossain, Mohammad Anwar ; Law, Isabella ; Burdick, Jane E. ; Willson, Timothy M. ; Brown, Peter J. ; Pearce, Kenneth H. ; Morales, Noah L. ; Perveen, Sumera ; Ghoshal, Anirban ; Asressu, Kesatebrhan Haile ; Popov, Konstantin I. ; Vala, Anand

Despite their widespread impact on human health, there are no approved drugs for combating alphavirus infections. The heterocyclic β-aminomethyl vinyl sulfone RA-0002034 (1a) is a potent irreversible covalent inhibitor of the alphavirus nsP2 cysteine protease with broad-spectrum antiviral activity. Analogs of 1a that varied each of the three regions of the molecule were synthesized to establish structure-activity relationships for the inhibition of Chikungunya (CHIKV) nsP2 protease and viral replication. The vinyl sulfone covalent warhead was highly sensitive to modifications. However, alterations to the core five-membered heterocycle and aryl substituent were well tolerated. The 5-(2,5-dimethoxyphenyl)pyrazole (1o) and 4-cyanopyrazole (8d) analogs exhibited k_inact/K_i ratios >9000 M^-1 s^-1. 3-Arylisoxazole (10) was identified as an isosteric replacement for the five-membered heterocycle, which circumvented the intramolecular cyclization of pyrazole-based inhibitors like 1a. A ligand-based model of the enzyme active site was developed to aid the design of nsP2 protease inhibitors as potential therapeutics against alphaviruses.

100 Deals associated with VEEV nsP2 inhibitors(The University of North Carolina at Chapel Hill)

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