Species Dependent Metabolism of a Covalent nsP2 Protease Inhibitor with Anti-alphaviral Activity.

RA-0002034 ( ) is a potent covalent inhibitor targeting the alphavirus nsP2 cysteine protease. The species-dependent pharmacokinetics and metabolism of were investigated to evaluate its therapeutic potential. Pharmacokinetic profiling revealed rapid clearance in mice, predominantly mediated by glutathione -transferase (GST)-catalyzed conjugation.

Structure-guided optimization of small molecules targeting the yeast casein kinase, Yck2, as a therapeutic strategy to combat Candida albicans.

is the most common cause of life-threatening fungal infection in the developed world but remains a therapeutic challenge. Protein kinases have been rewarding drug targets across diverse indications but remain untapped for antifungal development. Previously, screening kinase inhibitors against revealed a 2,3-aryl-pyrazolopyridine, GW461484A (GW), which targets casein kinase 1 (CK1) family member Yck2.

Chemoproteomic Profiling of for Characterization of Anti-fungal Kinase Inhibitors.

is a growing health concern as the leading causal agent of systemic candidiasis, a life-threatening fungal infection with a mortality rate of ~40% despite best available therapy. Yck2, a fungal casein kinase 1 (CK1) family member, is the cellular target of inhibitors YK-I-02 (YK) and MN-I-157 (MN). Here, multiplexed inhibitor beads paired with mass spectrometry (MIB/MS) employing ATP-competitive kinase inhibitors were used to define the selectivity of these Yck2 inhibitors across the global proteome.

Antimicrobial use before and during COVID-19: data from 108 Veterans Affairs medical centers.

Objective: Inpatient antibiotic use increased during the early phases of the COVID-19 pandemic. We sought to determine whether these changes persisted in persons with and without COVID-19 infection.

Design: Retrospective cohort analysis.

Identification of Inhibitors of virus nsP2 ATPase.

Non-structural protein 2 (nsP2), which plays an essential role in replication of CHIKV, contains a protease, helicase, and methyltransferase-like domain. We executed a simple a screen using malachite green to detect compounds that decreased ATP hydrolysis and tested a library of diverse compounds to find inhibitors of CHIKV nsP2 helicase.