Novel Plasmodial Surface Anion Channel Inhibitors as Antimalarial Drugs

DESCRIPTION provided by applicant The overall objective of this project is to generate new potent selective antimalarials that act through a novel mechanism of blocking the plasmodial surface anion channel PSAC a previously unexploited and highly conserved plasmodial target Human malaria is caused by five species of protozoan parasites in the genus Plasmodium It is estimated that there are more than million clinical cases of P falciparum malaria and over deaths annually with ninety percent of the deaths occurring in sub Saharan Africa The malaria parasites most importantly P falciparum require two hosts which are humans and female Anopheles mosquitoes Disease is transmitted to humans from the bite of an infected mosquito There are no effective vaccines available to prevent malaria but several small molecule treatment options exist such as chloroquine CQ and artemisinin CQ once the mainstay of malaria treatment has lost much of its efficacy because of mutations that confer resistance Resistance to artemisinin based therapy is now appearing in Southeast Asia New small molecule drugs especially those working on new targets that may be less susceptible to acquired resistance are desperately needed PSAC is a newly discovered essential antimalarial target which was recently validated by gene identification experiments The channel is produced by the parasite and inserts into the infected erythrocyte membrane It was demonstrated by Dr Sanjay Desai NIH that PSAC inhibitors discovered by high throughput screening kill parasites by direct action on this channel In preliminary studies Dr Desai developed and applied a screen for PSAC inhibitors using a sorbitol transport assay which resulted in the identification of several chemotypes that displayed inhibitory potencies K PSAC block in the nanomolar range Compounds also inhibited plasmodial growth with low nanomolar potencies IC Two of the andquot hit compoundandquot chemical scaffolds were chosen for medicinal chemistry optimization on the basis of their potency low cytotoxicity tractability of synthesis and overall favorable in vitro andquot drug likeandquot ADME results The first MBX was subjected to SAR evaluation in a Phase I SBIR project Compounds in this series demonstrated efficacy low toxicity and excellent in vitro ADME properties The Phase II project proposed here will focus on lead optimizing and scale up chemistry further mechanism of action studies and then in vivo pharmacokinetics and toxicology studies in preparation for efficacy testing We will test the efficacy of prioritized compounds in the humanized SCID mouse model to be conducted by Medicines for Malaria Venture MMV In Phase III we will conduct IND enabling preclinical studies to advance several of the most potent and least toxic compounds from the MBX scaffold The interdisciplinary approach which will merge the antimalarial expertise of Dr Desai and Dr Jeremy Burrows of MMV with the anti infective research and development capabilities of Microbiotix will produce inhibitors for a newly discovered essential and conserved malarial target and provide new treatment options for resistant infections PUBLIC HEALTH RELEVANCE Human malarial disease caused by parasites of the genus Plasmodium afflicts million and causes death in over people per year Although there are drugs available to treat the disease resistance is rapidly eroding their efficacy We propose to develop new antimalarial therapeutic agents that target an unexploited malarial anion channel protein to combat the growing resistance problem