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In particular, infections by\n                    <jats:italic>Cryptococcus neoformans<\/jats:italic>\n                    are associated with high mortality, emphasizing the need for novel therapeutic options. Calcineurin is a protein phosphatase that mediates fungal stress responses, and calcineurin inhibition by the natural product FK506 blocks\n                    <jats:italic>C. neoformans<\/jats:italic>\n                    growth at 37\u00b0C. Calcineurin is also required for pathogenesis. However, because calcineurin is conserved in humans and inhibition with FK506 results in immunosuppression, the use of FK506 as an anti-infective agent is precluded. We previously elucidated the structures of multiple fungal calcineurin-FK506-FKBP12 complexes and implicated the C-22 position on FK506 as a key point for differential modification of ligand inhibition of mammalian versus fungal target proteins. Through\n                    <jats:italic>in vitro<\/jats:italic>\n                    antifungal and immunosuppressive testing of FK520 (a natural analog of FK506) derivatives, we identified JH-FK-08 as a lead candidate for further antifungal development. JH-FK-08 exhibited significantly reduced immunosuppressive activity and both reduced fungal burden and prolonged survival of infected animals. JH-FK-08 exhibited additive activity in combination with fluconazole\n                    <jats:italic>in vivo<\/jats:italic>\n                    . These findings further advance calcineurin inhibition as an antifungal therapeutic approach.\n                  <\/jats:p>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>Fungal infections cause significant morbidity and mortality globally. The therapeutic armamentarium against these infections is limited, and the development of antifungal drugs has been hindered by the evolutionary conservation between fungi and the human host. With rising resistance to the current antifungal arsenal and an increasing at-risk population, there is an urgent need for the development of new antifungal compounds. The FK520 analogs described in this study display potent antifungal activity as a novel class of antifungals centered on modifying an existing orally active FDA-approved therapy. This research advances the development of much-needed newer antifungal treatment options with novel mechanisms of action.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.01810-23","type":"journal-article","created":{"date-parts":[[2023,9,22]],"date-time":"2023-09-22T09:01:21Z","timestamp":1695373281000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":6,"title":["Enhanced fungal specificity and\n                    <i>in vivo<\/i>\n                    therapeutic efficacy of a C-22-modified FK520 analog against\n                    <i>C. neoformans<\/i>"],"prefix":"10.1128","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0827-0788","authenticated-orcid":false,"given":"Angela","family":"Rivera","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Cancer Biology, Duke University Medical Center , Durham, North Carolina, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Won","family":"Young Lim","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Duke University , Durham, North Carolina, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eunchong","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Integrative Immunobiology, Duke University Medical Center , Durham, North Carolina, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0840-5147","authenticated-orcid":false,"given":"Patrick A.","family":"Dome","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Duke University , Durham, North Carolina, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3524-0699","authenticated-orcid":false,"given":"Michael J.","family":"Hoy","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University Medical Center , Durham, North Carolina, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivan","family":"Spasojevic","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Medical Center , Durham, North Carolina, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheng","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University Medical Center , Durham, North Carolina, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna Floyd","family":"Averette","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University Medical Center , Durham, North Carolina, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergio","family":"Pina-Oviedo","sequence":"additional","affiliation":[{"name":"Department of Pathology, Duke University Medical Center , Durham, North Carolina, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Praveen R.","family":"Juvvadi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Arkansas for Medical Sciences , Little Rock, Arkansas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William J.","family":"Steinbach","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Arkansas for Medical Sciences , Little Rock, Arkansas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Ciofani","sequence":"additional","affiliation":[{"name":"Department of Integrative Immunobiology, Duke University Medical Center , Durham, North Carolina, USA"},{"name":"Department of Molecular Genetics and Microbiology, Duke University Medical Center , Durham, North Carolina, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiyong","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Cancer Biology, Duke University Medical Center , Durham, North Carolina, USA"},{"name":"Department of Chemistry, Duke University , Durham, North Carolina, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph","family":"Heitman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Cancer Biology, Duke University Medical Center , Durham, North Carolina, USA"},{"name":"Department of Molecular Genetics and Microbiology, Duke University Medical Center , Durham, North Carolina, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.3390\/jof3040057"},{"key":"e_1_3_5_3_2","volume-title":"WHO fungal priority pathogens list to guide research, development and public health action","author":"World Health Organization","year":"2022","unstructured":"World Health Organization . 2022. 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