6 minute read
Dec. 28, 2023

AM-2-19: The 70-Year-Old Polyene Antifungal Class Gets an Upgrade

SF001 (AM-2-19)

IV ergosterol-extracting polyene antifungal Ph. I single-ascending dose portion completed from optimization of amphotericin B Nature, November 2023 University of Illinois, IL / Sfunga, MA

Drug Hunter Team

AM-2-19 (SF001), recently disclosed by the Burke lab in Nature, is an analog of the notoriously toxic IV antifungal drug, amphotericin B (AmB). Compared with AmB, AM-2-19 is significantly less toxic against primary human cells and in mice, while more broadly active against fungal pathogens including antifungal drug-resistant strains. Whereas AmB acts as a general steroid sponge, lethally extracting both fungal ergosterol (Erg) and human cholesterol (Chol) from cell membranes, AM-2-19 was designed and demonstrated to be specific for Erg, avoiding toxicities attributed to Chol extraction from healthy human cells. SF001 received Fast-Track Designation from the FDA in 2023 and has progressed to Ph. I clinical development.

This article highlights the history of antifungal polyene natural products, a new mechanistic hypothesis for polyene antibiotic activity, and the design of 3rd generation Erg-specific polyenes.



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