Repurposing and optimization of drugs for discovery of novel antifungals

Abstract

Although fungal diseases are a major and growing public health concern, there are only four major classes of drug to treat primary fungal pathogens. The pipeline of new antifungals in clinical development is relatively thin compared with other disease classes. One approach to rapidly identify and provide novel treatment options is to repurpose existing drugs as antifungals. However, such proposed drug-repurposing candidates often suffer suboptimal efficacy and pharmacokinetics (PK) for fungal diseases. Herein, we briefly review the current antifungal drug pipeline and recent approaches to optimize existing drugs into novel molecules with unique modes of action relative to existing antifungal drug classes.

Keywords: Anti-fungal drug development; Drug repurposing; Lead optimization; SOSA.

Figure 1.. (A) Examples of approved drugs for systemic fungal infections. (B) Current new antifungal drugs in clinical trials.

Figure 2.. Repurposing candidates from the Medicines for Malaria Venture Pathogen Box.

Figure 3.. Antimalarial drug mefloquine and analogs with more potent antifungal potency.

Chemical changes are colored blue. MICs reported for mefloquine and 4377 are from and for WR166391 from .

Figure 4.. FK506 and semi-synthetic derivative APX879.

Chemical differences are colored blue.

Figure 5.. Examples of recent antipsychotic drug SOSA efforts. (A) Fluphenazine and analog CWHM-974 with improved antifungal potency and reduced affinity for dopamine and serotonin receptors. (B) Haloperidol and analog B10 with improved antifungal potency and dopamine selectivity. (C) Sertraline and analog D16 with improved antifungal potency.

Chemical differences are colored blue.