Synthesis of a New Purine Analogue Class with Antifungal Activity and Improved Potency against Fungal IP_3-4K.

IF 4 2区医学 Q2 CHEMISTRY, MEDICINAL

ACS Infectious Diseases Pub Date : 2025-03-31 DOI:10.1021/acsinfecdis.4c00975

Desmarini Desmarini, Daniel Truong, Pooja Sethiya, Guizhen Liu, Bethany Bowring, Henning Jessen, Hue Dinh, Amy K Cain, Philip E Thompson, Julianne T Djordjevic

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引用次数: 0

Abstract

New antifungals are urgently needed to treat deadly fungal infections. Targeting the fungal inositol polyphosphate kinases IP_3-4K (Arg1) and IP₆K (Kcs1) is a promising strategy as it has been validated genetically to be crucial for fungal virulence but never pharmacologically. We now report the synthesis of DT-23, an analogue of N2-(m-trifluorobenzylamino)-N6-(p-nitrobenzylamino)purine (TNP), and demonstrate that it more potently inhibits recombinant Arg1 from the priority pathogen Cryptococcus neoformans (Cn) (IC₅₀ = 0.6 μM) than previous analogues (IC₅₀ = 10-30 μM). DT-23 also inhibits recombinant Kcs1 with similar potency (IC₅₀ = 0.68 μM) and Arg1 and Kcs1 activity in vivo. Unlike previous analogues, DT-23 inhibits fungal growth (MIC₅₀ = 15 μg/mL) and only 1.5 μg/mL synergizes with Amphotericin B to kill Cn in vitro. DT-23/Amphotericin B is also more protective against Cn infection in an insect model compared to each drug alone. Transcription profiling shows that DT-23 impacts early stages in IP synthesis and cellular functions impacted by IPK gene deletion, consistent with its targeted effect. This study establishes the first pharmacological link between inhibiting IPK activity and antifungal activity, providing tools for studying IPK function and a foundation to potentially develop a new class of antifungal drug.

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来源期刊

ACS Infectious Diseases CHEMISTRY, MEDICINALINFECTIOUS DISEASES&nb-INFECTIOUS DISEASES

CiteScore

9.70

自引率

3.80%

发文量

213

期刊介绍： ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to: * Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials. * Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets. * Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance. * Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents. * Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota. * Small molecule vaccine adjuvants for infectious disease. * Viral and bacterial biochemistry and molecular biology.