CAREER: Biosynthesis and Evolution of Pharmaceutical Leads

许多药物是以蛋白质为靶点的分子。该项目将建立一种方法，通过识别将抑制靶蛋白的分子，然后识别可以产生这种抑制剂的酶，为新药创造先导。最初的目标将与糖尿病、肥胖和癌症的治疗有关。 该项目开发的技术将通过快速发现和生物合成药物分子来加快药物开发的速度并降低成本。针对目前在STEM领域代表性不足的高中生的暑期生物技术培训计划将有助于培养高技能劳动力，而用于抑制剂鉴定和生产的教学和研究的核心设施将进一步加强药物开发。该项目代表着与当代利用微生物系统合成临床批准的药物及其前体的努力的重大背离。我们将对亲和力和活性的分子基础和热力学起源进行详细的研究。制定的结构-亲和力和结构-活性关系将被用来开发实验和计算方法的演变高亲和力的线索。这将产生用于评估酶之间功能相容性的结构限制的一般框架（即，它们合成、官能化和/或结合类似分子的能力），以及在这些限制内工作以构建新的抑制剂。最终目标是验证筛选代谢途径以产生具有靶向生物活性而不是靶向结构的分子的方法。如果成功的话，这个项目可以产生一个通用的和低成本的方法，使用合成生物学，以取代合成化学在铅的发展。这个奖项反映了NSF的法定使命，并已被认为是值得通过评估使用基金会的智力价值和更广泛的影响审查标准的支持。

Many drugs are molecules that target proteins. This project will establish an approach to create leads for new drugs by identifying molecules that will inhibit the target protein, then identifying enzymes that can produce this inhibitor. The initial targets will be relevant to the treatment of diabetes, obesity, and cancer. The technology developed in this project will accelerate the rate and lower the cost of drug development by enabling the rapid discovery and biological synthesis of the drug molecule. A summer biotechnology training program for high school students currently underrepresented in STEM will contribute to the development of a highly-skilled workforce, and a core facility for teaching and research on inhibitor identification and production will further enhance drug development.This project represents a significant departure from contemporary efforts to use microbial systems for the synthesis of clinically approved drugs and their precursors. We will carry out a detailed study of the molecular basis and thermodynamic origin of affinity and activity. The structure-affinity and structure-activity relationships formulated will be exploited to develop experimental and computational methods for the evolution of high-affinity leads. This will result in a general framework for assessing the structural limits of functional compatibility between enzymes (i.e., their ability to synthesize, functionalize, and/or bind similar molecules), and for working within those limits to build new inhibitors. The ultimate goal is to validate the approach of screening metabolic pathways to produce molecules with targeted biological activities rather than targeted structures. If successful, this project could yield a general and low-cost approach for using synthetic biology to replace synthetic chemistry in lead development.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.