Novel and Effective Antifungal Compounds Derived from Molecular Field Analysis

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Invasive fungal infections are an increasingly common and serious cause of illness and death in the U.S. and worldwide. Infection by Candida albicans has increased tenfold to become more frequent than diseases caused by E. coli and Pseudomonas, and it has become one of the most common fatal infections in the United States. Clinical management of invasive fungal infections is significantly constrained, and the search for new drugs represents a major challenge to mycotic disease research. Currently available treatments have significant drawbacks, including serious side effects and the emergence of pathogen resistance. There is a significant need for new orally-deliverable drugs effective against specific fungal species as well as compounds exhibiting broad-spectrum antifungal activity. Compounds demonstrating a novel mode of action against previously untapped molecular targets are highly desirable. Here we apply HarvestTM, a proprietary drug discovery platform, to identify inhibitors of a proven antifungal target, acetyl-CoA carboxylase (ACCase). A potent inhibitor of this target currently exists, the natural product soraphen A, but difficulty in large-scale manufacture and possible toxicity concerns have prevented its use as a pharmaceutical treatment. We have used Harvest's molecular modeling technology to computationally screen a database of over four million compounds and identify those most likely to bind at the same site as soraphen. These will be ranked based on their similarity to soraphen's molecular field pattern and filtered for characteristics indicative of successful anti-infectives. The resulting compounds will be acquired and evaluated in the laboratory for activity against pathogenic fungi such as Candida and for biochemical inhibition of the target enzyme. Active compounds will be titrated and the activity of available analogs will be confirmed. It is anticipated that 20-50 active compounds will result from these screens, facilitating further model refinements and the acquisition/synthesis of more efficacious analogs for each scaffold. During Phase II, it is anticipated that 1-3 chemical scaffolds will be prioritized and moved into spectrum testing against additional fungal species, preliminary toxicology testing, and evaluation in animal models. The most effective compounds based on a broad set of criteria would then advance into pre-clinical development and clinical trials. PUBLIC HEALTH RELEVANCE: Invasive fungal infections are an increasingly common and serious cause of illness and death in the U.S. and worldwide; for example, Candida has become one of the most common fatal pathogens in the United States. HarvestTM, a proprietary drug discovery platform, is applied to identify novel inhibitors of a proven antifungal target. Using the molecular field pattern of a known inhibitor that exhibits some drawbacks for drug development, a database of commercially available compounds is screened and assayed in vitro against pathogenic fungi to find chemical leads which are predicted to overcome these drawbacks.