Project Grant R35GM155161

CONVERGENT EVOLUTION IN NATURAL PRODUCT BIOSYNTHESIS - ABSTRACT NATURAL PRODUCTS ARE NON-ESSENTIAL SMALL ORGANIC MOLECULES PRODUCED BY LIVING ORGANISMS, SUCH AS BACTERIA, FUNGI, PLANTS, AND ANIMALS. THEY HAVE BEEN DESCRIBED AS THE MOST IMPORTANT STRUCTURAL LEADS WITHIN THE PHARMACEUTICAL INDUSTRY, AND CURRENT ESTIMATES SUGGEST THAT 50-70% OF MEDICINES CAN BE TRACED BACK TO A NATURAL PRODUCT ORIGIN, INCLUDING MORE THAN 60% OF THE ANTICANCER DRUGS BROUGHT TO MARKET IN THE LAST 25 YEARS. ONE OF THE FIRST MAJOR HURDLES IN ANY DRUG DEVELOPMENT PROGRAM INVOLVES AN INITIAL "HIT IDENTIFICATION", A PROCESS COMMONLY ACCOMPLISHED THROUGH LARGE-SCALE SCREENING PROGRAMS. CONSEQUENTLY, ESTABLISHING A NEW NATURAL PRODUCT-DRIVEN APPROACH TO DRUG-LEAD IDENTIFICATION HAS THE POTENTIAL TO MARKEDLY IMPROVE THE EFFICIENCY OF THE DRUG DEVELOPMENT PROCESS. TO THIS END, HEREIN WE INTRODUCE A NEW STRATEGY THAT ATTEMPTS TO SHIFT THE BURDEN OF HIT IDENTIFICATION FROM SCIENTIST TO NATURE. SPECIFICALLY, WE PROPOSE THAT INSTANCES OF "CONVERGENT EVOLUTION" IN NATURAL PRODUCT BIOSYNTHESIS MAY BE A MARKER FOR MOLECULES OF SIGNIFICANT BIOLOGICAL IMPORTANCE GIVEN THEY HAVE SURVIVED THE NATURAL SELECTION PROCESS ON MORE THAN ONE OCCASION. SELECTION OF OUR TARGETS, THE HALENAQUINONES, VIRIDINS, WORTMANNINS, AND HIBISCONES, WAS GUIDED BY A COMBINATION OF BIOSYNTHETIC CONSIDERATIONS AND PREESTABLISHED ANTICANCER ACTIVITIES. WE HAVE ALREADY DEVELOPED AN INNOVATIVE AND SCALABLE ROUTE TO MANY OF HALENAQUINONE FAMILY MEMBERS. OUR APPROACH TAKES ADVANTAGE OF THE INHERENT REACTIVITY PRESENT WITHIN THESE MOLECULES, AND WHEN CONSIDERED ALONGSIDE THE SIMPLE NATURE OF THE REAGENTS EMPLOYED AND THE STRUCTURE OF THE VARIOUS COISOLATES, WE BELIEVE THIS TO BE IN SUPPORT OF OUR BIOSYNTHETIC SPECULATION. WE HAVE ALREADY DEMONSTRATED OUR APPROACH IS DIRECTLY APPLICABLE TO THE SYNTHESIS OF SIMPLIFIED ANALOGUES, AND WE ENVISION IT WILL TRANSLATE TO OUR REMAINING NATURAL PRODUCT FAMILIES. THE FIRST EXHAUSTIVE SAR STUDIES, DONE IN COMBINATION WITH COMPUTATIONAL AND EXPERIMENTAL DOCKING STUDIES, WILL INFORM THE DEVELOPMENT OF NEW ANTI-CANCER DRUG LEADS AND SIMPLIFIED CHEMICAL PROBES. IN THE LONG-TERM, IT IS ENVISIONED INSTANCES OF "CONVERGENT EVOLUTION" IN NATURAL PRODUCT BIOSYNTHESIS MAY DEVELOP IN TO A GENERAL APPROACH TO DRUG DISCOVERY.