Structure-Guided Discovery of Potent Antifungals that Prevent Ras Signaling by Inhibiting Protein Farnesyltransferase

You Wang, Feng Xu, Connie B. Nichols, Yuqian Shi, Homme W. Hellinga, J. Andrew Alspaugh, Mark D. Distefano, Lorena S. Beese

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Infections by fungal pathogens are difficult to treat due to a paucity of antifungals and emerging resistances. Next-generation antifungals therefore are needed urgently. We have developed compounds that prevent farnesylation of Cryptoccoccus neoformans Ras protein by inhibiting protein farnesyltransferase with 3-4 nanomolar affinities. Farnesylation directs Ras to the cell membrane and is required for infectivity of this lethal pathogenic fungus. Our high-affinity compounds inhibit fungal growth with 3-6 micromolar minimum inhibitory concentrations (MICs), 4- to 8-fold better than Fluconazole, an antifungal commonly used in the clinic. Compounds bound with distinct inhibition mechanisms at two alternative, partially overlapping binding sites, accessed via different inhibitor conformations. We showed that antifungal potency depends critically on the selected inhibition mechanism because this determines the efficacy of an inhibitor at low in vivo levels of enzyme and farnesyl substrate. We elucidated how chemical modifications of the antifungals encode desired inhibitor conformation and concomitant inhibitory mechanism.

Original languageEnglish (US)
Pages (from-to)13753-13770
Number of pages18
JournalJournal of medicinal chemistry
Volume65
Issue number20
DOIs
StatePublished - Oct 27 2022

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health via PO1-Al104533 (to L.S.B., J.A.A., M.D.D.) and R35-GM141853 (M.D.D.).

Funding Information:
Data were collected at Southeast Regional Collaborative Access Team (SER-CAT) 22-ID (or 22-BM) beamline at the Advanced Photon Source, Argonne National Laboratory. SER-CAT is supported by its member institutions and equipment grants (S10_RR25528, S10_RR028976, and S10_OD027000) from the National Institutes of Health. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38. Data were also collected at Beamline 8.3.1 of the Advanced Light Source, a U.S. DOE Office of Science User Facility under Contract No. DE-AC02-05CH11231, is supported in part by the ALS-ENABLE program funded by the National Institutes of Health, National Institute of General Medical Sciences, grant P30 GM124169-01. Structural biology applications used in this project were compiled and configured by SBGrid. The authors thank Holly Kim for assistance with determining IC values. 1μM 50 1

Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.

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