A Computational Approach to Developing Heterochiral Peptide Therapeutics

描述（由申请人提供）：多肽是一种新兴和重要的治疗药物，市场上有超过40种化合物，近700种处于临床或临床前试验中。在多肽药物的开发过程中，经常加入氨基酸的d -对映体，通过降低对蛋白质水解的敏感性来改善药代动力学和药效学特性。通常，这种修饰是通过试错或组合方法引入先导化合物的。我们的实验室正在开发protecad（蛋白质计算机辅助设计）来模拟非天然氨基酸对结构和稳定性的影响。利用蛋白质设计的基本原理，我们将追求具有可变手性的多肽的计算，基于结构的开发，广泛扩展我们创造安全和有效治疗方法的能力。当前计算蛋白质设计软件的成功归功于几十年来对天然蛋白质的结构和热力学研究。这就引出了一个重要的问题——这些程序所使用的模拟工具和分子参数集是否可以推广到更广泛的大分子设计中？我们实验室对几种计算设计的异手性蛋白质的初步表征表明，protCAD中的工具可扩展到非天然氨基酸。在专注于立体化学多样化多肽，我们将严格测试我们的基本理解原理的蛋白质结构和稳定性。我们的具体目标是利用我们实验室开发的protCAD和结构生物信息学工具的组合鉴定出三种合理设计的异手性铅支架。每个支架都提出了独特的生物物理挑战，探索分子力和折叠能量景观在设计中的贡献。这些支架解决了重要的公共卫生优先事项，包括：(1)开发治疗糖尿病的有效疗法，(2)为有毒金属中毒的螯合治疗提供更安全的分子，(3)提供一种新型的、合理设计的抗菌素。

DESCRIPTION (provided by applicant): Peptides are an emergent and important class of therapeutics with over forty compounds on the market and nearly 700 more in clinical or pre-clinical trials. During the development of peptide drugs, D-enantiomers of amino acids are frequently incorporated to improve pharmacokinetic and pharmacodynamic properties by lowering susceptibility to proteolysis. Typically, such modifications are introduced in lead compounds by trial-and-error or combinatorial approaches. Our laboratory is developing protCAD (protein Computer Aided Design) to simulate the impact of non-natural amino acids on structure and stability. Using fundamental principles of protein design, we will pursue the computational, structure-based development of peptides with variable chirality, broadly extending our capacity to create safe and potent therapeutics. The success of current computational protein design software is indebted to decades of structural and thermodynamic studies on natural proteins. This leads to an important question - Can simulation tools and molecular parameter sets these programs employ be generalized to the design of a broader class of macromolecules? Preliminary characterization of several computationally designed heterochiral proteins in our lab indicates that tools in protCAD are extendable to non-natural amino acids. In focusing on stereochemically diverse peptides, we will stringently test our fundamental understanding of principles underlying protein structure and stability. Our specific aims focus on three rationally designed, heterochiral lead scaffolds identified using a combination of protCAD and structural bioinformatics tools developed in our laboratory. Each scaffold presents a unique biophysical challenge, exploring contributions of molecular forces and the folding energy landscape in design. These scaffolds address important public health priorities including: (1) developing potent therapeutics for the treatment of diabetes, (2) providing safer molecules for chelation therapy treatment of toxic metal poisoning and (3) providing a novel, rationally designed class of antimicrobials. PUBLIC HEALTH RELEVANCE: We are developing software for the computer-based drug design of peptide therapeutics. Currently, we are focusing our program on three major areas of public health concern. The first is an anti- diabetes peptide hormone that stimulates insulin production and lowers blood sugar. We are also developing peptides that bind toxic metals to promote their safe clearance from the body. Lastly, we are adapting a natural peptide from soil bacteria to produce a new class of antibiotics. Computer engineering of peptide drugs has a lot to contribute both to medicine and to our basic understanding of how proteins function.