A Computational Approach to Developing Heterochiral Peptide Therapeutics

描述（由申请人提供）：肽是一种新兴且重要的治疗药物，市场上有超过40种化合物，临床或临床前试验中有近700种。在肽类药物的开发过程中，经常掺入氨基酸的D-对映体，以通过降低对蛋白水解的敏感性来改善药代动力学和药效学特性。通常，通过试错法或组合方法将此类修饰引入先导化合物中。我们的实验室正在开发ProtCAD（蛋白质计算机辅助设计），以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数十年来对天然蛋白质的结构和热力学研究。这导致了一个重要的问题-这些程序采用的模拟工具和分子参数集可以推广到更广泛的大分子设计吗？我们实验室中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性肽，我们将严格测试我们的基本原则的蛋白质结构和稳定性的理解。我们的具体目标集中在三个合理设计的，异手性铅支架使用protCAD和我们实验室开发的结构生物信息学工具相结合确定。每个支架都提出了一个独特的生物物理挑战，探索分子力和折叠能量在设计中的贡献。这些支架解决了重要的公共卫生优先事项，包括：（1）开发用于治疗糖尿病的有效治疗剂，（2）为有毒金属中毒的螯合治疗提供更安全的分子，以及（3）提供新型，合理设计的抗菌剂。 公共卫生相关性：我们正在开发基于计算机的肽治疗药物设计软件。目前，我们的计划集中在三个主要的公共卫生领域。第一种是一种抗糖尿病肽激素，它能刺激胰岛素的产生，降低血糖.我们还在开发结合有毒金属的肽，以促进它们从体内安全清除。最后，我们正在利用土壤细菌中的天然肽来生产一类新的抗生素。肽药物的计算机工程对医学和我们对蛋白质功能的基本理解都有很大贡献。

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.