Fungal infections have increased dramatically in recent years to become important causes of mortality in hospitalized patients. The increase in life-threatening fungal infections has brought about an increased use of antifungal drugs and a pressing need for new, broad-spectrum, fungicidal agents that can be used empirically in immunocompromised patients e.g., AIDS and organ transplant patients. There is still a treatment failure of more than 50% among patients with acute invasive aspergillosis, and a 20 to 30% failures with candidemia. Current available therapies for treating fungal infections often suffer from drug-related toxicity, hazardous drug-drug interactions, non-optimal pharmacokinetics, and development of drug resistance. Preliminary studies have shown that several peptides from our chemical library have antifungal activity against Rhodotorula pilimanae, a nonpathogenic fungus. Three of the compounds tested so far showed activity against Candida albicans. These peptides are found to be nontoxic in several human and monkey cell lines and therefore show promise for further pursuing. It is proposed to conduct antifungal activity studies on all the peptides against Candida, Aspergillus, and Cryptococcus, the fungi of clinical importance.
The specific aims of Phase I studies are (a) resynthesize all the compounds, (b) evaluate compounds for antifungal activity against Candida, Aspergillus, and Cryptococcus, (c) determine minimum inhibitory concentrations and minimum fungicidal concentrations, and (d) conduct in vivo experiment on the most promising compound against Candida, Aspergillus, and Cryptococcus. These experiments will include inhibition of colony forming incidences and survival of mice. Based on the data obtained in Phase I studies, Phase II studies will focus on designing metabolically stable analogs for oral activity using computer-based molecular modeling, developing pharmacologically-based and physiologic-based appropriate administration strategies, conduct extensive in vivo studies, determine the mechanism of action; conduct toxicology and pharmacokinetic studies, and file IND. The data generated by these studies will provide important information to raise this technology to a level of maturity where it can compete successfully for commercial funding to bring a new class of antifungal drugs to clinical use.
