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Duke University

Proc. Natl. Acad. Sci. USA, Jan 07 2025, 122 (1) | https://doi.org/10.1073/pnas.2419883121 Structure-guided design and synthesis of C22- and C32-modified FK520 analogs with enhanced activity against human pathogenic fungi

Patrick A. Dome^a, Pyeonghwa Jeong^a,1, Gibeom Nam^b,1, Hongjun Jang^a, Angela Rivera^c, Anna Floyd Averette^d, Eunchong Park^e, Tzu-Chieh Liao^e, Maria Ciofani^d,e, Jianli Wu^d, Jen-Tsan Ashley Chi^d, Ronald A. Venters^f,g, Hyun-Ju Park^b, William J. Steinbach^h, Praveen R. Juvvadi^h, Joseph Heitman^c,d,2, and Jiyong Hong^a,c,2

^aDepartment of Chemistry, Duke University, Durham, NC 27708
^bSchool of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
^cDepartment of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710
^dDepartment of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710
^eDepartment of Integrative Immunobiology, Duke University Medical Center, Durham, NC 27710
^fDuke University Nuclear Magnetic Resonance Center, Duke University, Durham, NC 27710
^gDepartment of Radiology, Duke University Medical Center, Durham, NC 27710
^hDepartment of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202

¹P.J. and G.N. contributed equally to this work.
²To whom correspondence may be addressed.

Abstract

Invasive fungal infections are a leading cause of death worldwide. Translating molecular insights into clinical benefits is challenging because fungal pathogens and their hosts share similar eukaryotic physiology. Consequently, current antifungal treatments have limited efficacy, may be poorly fungicidal in the host, can exhibit toxicity, and are increasingly compromised by emerging resistance. We have established that the phosphatase calcineurin (CaN) is required for invasive fungal disease and an attractive target for antifungal drug development. CaN is a druggable target, and there is vast clinical experience with the CaN inhibitors FK506 and cyclosporin A (CsA). However, while FK506 and its natural analog FK520 exhibit antifungal activity, they are also immunosuppressive in the host and thus not fungal-selective. We leverage our pathogenic fungal CaN-FK506-FKBP12 complex X-ray structures and biophysical data to support structure-based ligand design as well as structure-activity relationship analyses of broad-spectrum FK506/FK520 derivatives with potent antifungal activity and reduced immunosuppressive activity. Here, we apply molecular docking studies to develop antifungal C22- or C32-modified FK520 derivatives with improved therapeutic index scores. Among them, the C32-modified FK520 derivative JH-FK-44 (7) demonstrates a significantly improved therapeutic index compared to JH-FK-08, our lead compound to date. NMR binding studies with C32-derivatives are consistent with our hypothesis that C32 modifications disrupt the hydrogen bonding network in the human complex while introducing favorable electrostatic and cation-π interactions with the fungal FKBP12 R86 residue. These findings further reinforce calcineurin inhibition as a promising strategy for antifungal therapy.

논문정보

형식Research article
게재일2025년 01월 (BRIC 등록일 2025-01-06)
연구진국내+국외 연구진
분야 바이오·의료융합 > 다학제 융합/복합

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