A First-in-class Inhibitor of Hsp110 Molecular Chaperones of Pathogenic Fungi

Overview

Journal Nat Commun

Specialty Biology

Date 2023 May 12

PMID 37173314

Authors

Liqing Hu

Cancan Sun

Justin M Kidd

Jizhong Han

Xianjun Fang

Hongtao Li

Qingdai Liu

Aaron E May

Qianbin Li

Lei Zhou

Qinglian Liu

Affiliations

Soon will be listed here.

Abstract

Proteins of the Hsp110 family are molecular chaperones that play important roles in protein homeostasis in eukaryotes. The pathogenic fungus Candida albicans, which causes infections in humans, has a single Hsp110, termed Msi3. Here, we provide proof-of-principle evidence supporting fungal Hsp110s as targets for the development of new antifungal drugs. We identify a pyrazolo[3,4-b] pyridine derivative, termed HLQ2H (or 2H), that inhibits the biochemical and chaperone activities of Msi3, as well as the growth and viability of C. albicans. Moreover, the fungicidal activity of 2H correlates with its inhibition of in vivo protein folding. We propose 2H and related compounds as promising leads for development of new antifungals and as pharmacological tools for the study of the molecular mechanisms and functions of Hsp110s.

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