Exploring 2-Biaryl-ELQs for Targeting the Qo and Qi sites of P. falciparum cyt. bc1

Portland Va Medical Center, Portland OR

Investigators

Linked publications, trials & patents

Abstract

Background and Innovation: Malaria is a potentially fatal tropical disease spread from person- to-person by Anopheles mosquitoes. Over 200 million clinical cases of malaria occur around the world each year along with roughly 600,000 deaths. The global situation is worsening due to widespread resistance to virtually all drugs that have been put into clinical use. This application seeks support for research to optimize the 2-arylquinolone scaffold for targeting of the Plasmodium falciparum cytochrome bc1 complex, an ideal target given its critical importance to parasite survival in the liver, blood and vector stages of its life cycle. Significance and Impact to Veterans Healthcare: Malaria and antimalarial drugs are two of the most common biological and chemical exposures of US warfighters. Our long-term goal is to develop a 2-arylquinolone to provide protection against multidrug resistant malaria parasites. Given our experience we believe that we can design 2-arylquinolones to selectively inhibit the malarial cytochrome bc1 complex, a privileged target that is critical to the survival of the parasite in all life cycle stages of development. We will design of 2-arylquinolones to provide a preclinical candidate for use is preventing and treating malaria in humans. Optimized drugs could be delivered by once-weekly or optimally once-monthly oral dosing to improve compliance or by long-acting injectable formulation for seasonal protection against disease. Protection against malaria avoids the potential for toxic exposures to fever, seizures, and high drug levels that might otherwise have negative and long-term side effects for soldiers and veterans. Path to translation/implementation: We have previously discovered and developed lead candidate drug molecules that have advanced to preclinical status and ultimately on to clinical development by the Medicines for Malaria Venture: ELQ-300 and ELQ-331. More recently, ELQ-596 and its prodrug ELQ-598 have been taken up by the MMV and advanced to pipeline status. Our vision is to identify a gap in knowledge or treatment and to work toward filling the need. Here we seek to develop a 2-arylquinolone that targets a critical enzyme in the parasite’s electron transport pathway and that works synergistically and operationally together with other anti-respiratory drugs including the ELQs and clinical drug atovaquone. We envision a cocktail of anti-respiratory drugs, including an ELQ and an optimized 2-arylquinolone, that can be used in mass administration campaigns to support the worldwide eradiation of malaria. Our current path to translation of our findings to a clinical candidate involve partnering with the Medicines for Malaria Venture and/or the Division of Experimental Therapeutics at Walter Reed Army Institute of Research for advancement to clinical studies.