Project Grant F32AI186457

CHEMOENZYMATIC TOTAL SYNTHESIS OF PENTAENE ANTIFUNGALS AND ANALOG DEVELOPMENT - PROJECT SUMMARY/ABSTRACT INFECTIONS CAUSED BY THE FUNGI CANDIDA AND ASPERGILLUS AFFECT MORE THAN ONE BILLION PEOPLE EACH YEAR. WHILE OFTEN NOT LIFE THREATENING, THESE INFECTIONS ARE MUCH MORE SEVERE WHEN THEY BECOME INVASIVE. INVASIVE INFECTIONS ARE EXCEPTIONALLY DEADLY IN PATIENTS UNDERGOING CHEMOTHERAPY OR WHO ARE OTHERWISE IMMUNODEFICIENT, AND CURRENT CLINICAL METHODS FOR THE TREATMENT OF INVASIVE FUNGAL INFECTIONS ARE INEFFECTIVE OR CAUSE COMPLICATIONS DUE TO OFF-TARGET TOXICITY. THIS RESULTS IN AN ANNUAL DEATH TOLL EXCEEDING 1.5 MILLION. AS SUCH, THE WORLD HEALTH ORGANIZATION (WHO) AND THE NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES (NIAID) HAVE IDENTIFIED RESEARCH SUPPORTING THE DEVELOPMENT OF NOVEL ANTIFUNGALS AS CRITICALLY IMPORTANT. THE RESEARCH PROPOSED IN THIS FELLOWSHIP WILL LEVERAGE CHEMOENZYMATIC TOTAL SYNTHESIS TO ACCESS PENTAENE ANTIFUNGALS IN A CONCISE AND MODULAR MANNER. THE CENTRAL HYPOTHESIS OF THIS RESEARCH PLAN IS THAT RATIONAL DESIGN OF NEW ANALOGS THAT CAN BE ACCESSED ONLY THROUGH CHEMICAL SYNTHESIS WILL AFFORD ANTIFUNGALS THAT RIVAL THE CURRENT CLINICAL STANDARD. THE PROPOSED SYNTHETIC STRATEGY RELIES ON AN ENZYMATIC ALDOL REACTION, BIDIRECTIONAL CHAIN EXTENSION, AND DESYMMETRIZATION TO DELIVER THE ALL-SYN BACKBONE PRESENT IN THE FILIPINS AND PENTAMYCIN. LATE-STAGE MACROCYCLIZATION WILL AVOID STABILITY CONCERNS ARISING FROM THE SENSITIVE PENTAENE MOTIF. FINALLY, CHEMOENZYMATIC OXIDATIONS WILL BE PERFORMED TO DELIVER THREE DIFFERENT PENTAENE NATURAL PRODUCTS. FURTHERMORE, WE PROPOSE A NOVEL ENZYMATIC MIX-AND-MATCH STRATEGY TO DELIVER DIFFERENT PARTIALLY OXIDIZED POLYENES THAT ARE NOT PRODUCED IN NATURE. THIS CHEMOENZYMATIC APPROACH WILL ENABLE THE DEVELOPMENT OF ANALOGS THAT CONTAIN MODIFICATIONS TO HYDROXYL GROUPS ALONG THE POLYOL BACKBONE, OR TO THE POLYENE MOTIF. THE FIRST CLASS OF ANALOGS IS DESIGNED TO PROBE HYDROGEN-BONDING TO ENHANCE ERGOSTEROL-BINDING SELECTIVITY AND AVOID HUMAN TOXICITY. THE SECOND CLASS IS DESIGNED TO INVESTIGATE P-STACKING, THEREBY MODIFYING SPECIFICITY AND STABILITY OF THE POLYENE ANTIFUNGALS. FINALLY, HYBRID ANALOGS THAT COMBINE THE MODIFICATIONS PRESENT IN BOTH CLASSES WILL BE SYNTHESIZED TO ACCESS THE IDEAL ANTIFUNGAL. ALL TOLD, ACCESS TO DOZENS OF ANALOGS THROUGH THE SAME ROUTE WILL ELUCIDATE STRUCTURE-ACTIVITY RELATIONSHIPS AND INFORM RATIONAL DESIGN OF NEW ANTIFUNGALS FOR THE BROADER SCIENTIFIC COMMUNITY. THE APPLICANT'S LONG-TERM GOALS ARE TO ENGAGE IN RESEARCH AT THE INTERFACE OF CHEMISTRY AND BIOLOGY TO SOLVE PROBLEMS THAT ARE CHALLENGING TO ADDRESS WITH EITHER DISCIPLINE INDEPENDENTLY. THIS FELLOWSHIP WILL ALLOW THE APPLICANT TO FURTHER IMPROVE THEIR SKILLS IN CHEMICAL SYNTHESIS WHILE LEARNING NEW TECHNIQUES IN ENZYMOLOGY, BIOLOGY, AND MEDICINAL CHEMISTRY. THE FELLOWSHIP WILL ALSO STRENGTHEN THE APPLICANT'S SKILLS IN MENTORING, TEACHING, AND COMMUNICATION SO THAT THEY CAN HAVE A SUCCESSFUL INDEPENDENT CAREER TRAINING JUNIOR SCIENTISTS IN ORGANIC CHEMISTRY. THIS WILL PROVIDE YOUNG SCIENTISTS WITH THE TOOLSET NECESSARY TO WORK AT THE INTERFACE OF ORGANIC CHEMISTRY AND OTHER IMPACTFUL FIELDS.