Project Grant K43TW012015

MULTI-TARGET APPROACH TO RATIONAL DESIGN OF NOVEL THERAPEUTICS FOR HUMAN AFRICAN TRYPANOSOMIASIS - PROJECT SUMMARY THIS PROPOSAL AIMS TO DEVELOP SAFER AND EFFECTIVE DRUG FOR THE TREATMENT OF HUMAN AFRICAN TRYPANOSOMIASIS (HAT), AN INFECTIOUS DISEASE THAT ARE ENDEMIC TO SUB-SAHARAN AFRICA. HAT IS OF GLOBAL HEALTH CONCERNS DUE TO THE LACK OF HOPE FOR PREVENTION BY VACCINATION AND THE UNSATISFACTORY TREATMENT OPTIONS. THERE IS NEED FOR THE DEVELOPMENT OF NEW DRUGS WITH NOVEL MECHANISM OF ACTION. TO RATIONALLY DEVELOP A GOOD DRUG, IT IS IMPORTANT TO IDENTIFY MOLECULAR TARGETS IN THE PARASITES. THESE TARGET MOLECULES SHOULD FULFILL THE FOLLOWING CRITERIA: (I) IMPORTANT FOR THE PARASITES' SURVIVAL, (II) ABSENT IN HUMANS OR NOT IMPORTANT IN HUMANS, AND (III) IF PRESENT IN HUMANS, IT SHOULD BE STRUCTURALLY DIFFERENT FROM THE HUMAN MOLECULE. AFTER WHICH WE CAN THEN SEARCH FOR CHEMICAL COMPOUNDS THAT CAN SPECIFICALLY INTERACT WITH THE TARGET MOLECULES TO STOP THEM FROM FUNCTIONING, AND EVENTUALLY KILLING THE PARASITES. THE ENERGY (ATP) METABOLISM PATHWAY OF BLOOD STREAM FORMS OF THE TRYPANOSOMES (BSFS) PRESENTS SUCH A NOVEL TARGET FOR DRUG DISCOVERY BECAUSE IT DIFFERS FROM THAT OF ANIMALS. WE HAVE IDENTIFIED TWO INTERESTING TARGET PROTEINS IN THE PARASITES THAT ARE IMPORTANT FOR THEIR ENERGY GENERATION AND SURVIVAL IN THE HUMAN HOST; THESE ARE THE TRYPANOSOMAL ALTERNATIVE OXIDASE (TAO) AND GLYCEROL KINASE (TGK). HOWEVER, BOTH ENZYMES MUST BE SIMULTANEOUSLY BLOCKED IN ORDER TO EFFECTIVELY KILL THE PARASITES AND CURE THE INFECTION. TAO IS ABSENT IN HUMANS; ALTHOUGH TGK IS PRESENT, THE STRUCTURE REVEALED THAT SOME FUNCTIONAL REGIONS ARE VERY DIFFERENT FROM GK OF OTHER ORGANISMS, PROVIDING ENCOURAGING PRELIMINARY DATA TOWARDS SUCCESSFUL DEVELOPMENT OF TGK-SPECIFIC INHIBITOR(S). THE CO-ADMINISTRATION OF TGK AND TAO INHIBITORS WILL SELECTIVELY KILL THE PARASITE AND LIKELY AVOIDING TOXICITY ISSUES. ONE OF THE INNOVATIONS IN OUR PROPOSAL IS THAT WE AIM TO DESIGN SINGLE INHIBITORS THAT CO-TARGET TAO AND TGK. THIS WILL AVOID THE CHANCES OF DRUG-DRUG INTERACTION VERSUS UNDESIRABLE SIDE EFFECT THAT READILY ACCOMPANIES ADMINISTRATION OF MULTIPLE DRUGS TO TREAT A DISEASE. THIS WILL BE ACHIEVED BY EXPERIMENTAL SCREENING OF THE 100,000 COMPOUNDS IN THE LIBRARIES OF SMALL MOLECULE REPOSITORY OF SKAGGS SCHOOL OF PHARMACY AND PHARMACEUTICAL SCIENCES (SSPPS), UNIVERSITY OF CALIFORNIA SAN DIEGO (UCSD), USA AGAINST THE ENZYMATIC ACTIVITIES OF TGK AND TAO AND THEN SELECTING THOSE DISPLAYING INHIBITORY CAPABILITY AGAINST BOTH ENZYMES. IN PARALLEL, THE COMPOUNDS WILL ALSO BE SCREENED AGAINST THE PARASITE FOR IDENTIFYING THOSE WITH TRYPANOSOMES KILLING EFFECTS. BOTH CATEGORY OF COMPOUNDS WILL THEN BE OPTIMIZED FOR KILLING THE TRYPANOSOMES IN CULTURE, FOR INHIBITION OF TAO AND TGK, AND FOR LACK OF EFFECTS ON HUMAN GLYCEROL KINASE AND CULTURED HUMAN CELLS. OVERALL, THE PRESENT PROPOSAL WILL LEAD TO THE DESIGN SINGLE NON-TOXIC AND EFFECTIVE TRYPANOCIDAL COMPOUND(S). THE PI, EMMANUEL O. BALOGUN, PHD, WILL COLLABORATE ON THIS PROJECT WITH A TEAM OF MULTIDISCIPLINARY EXPERTS IN USA AND NIGERIA: AT SSPPS UCSD PROFESSORS JAMES H. MCKERROW (USA LEAD MENTOR), LARISSA PODUST AND JAIR SIQUEIRA-NETO (USA CO-MENTORS); PROFESSORS MAMMAN MOHAMMED (NIGERIA LEAD MENTOR), CHRISTIAN HAPPI, MARYAM AMINU, AND MOHAMMED N SHUAIBU (NIGERIA CO-MENTORS).