A Computational Approach to Developing Heterochiral Peptide Therapeutics

开发异手性肽疗法的计算方法

基本信息

批准号：
7899429
负责人：
Vikas Nanda
金额：
$ 30.3万
依托单位：
UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7899429
关键词：
Address Affinity Amino Acid Substitution Amino Acids Antibiotics Area Arsenic Bacillus brevis Bacteria Benchmarking Binding Bioinformatics Biological Factors Blood Glucose Cadmium Cations Chelation Therapy Clinical Cobalt Complex Computer-Aided Design Computers Databases Development Diabetes Mellitus Drug Design Drug Kinetics Elements Engineering Glutamine Gramicidin Hand Hormones Hydrogen Bonding Insulin Ion Channel Laboratories Lead Left Ligands Marketing Medicine Mercury Metals Modeling Modification Molecular Molecular Conformation Peptides Pharmaceutical Preparations Pharmacodynamics Predisposition Production Property Proteins Proteolysis Public Health Resolution Series Simulate Site Software Design Soil Specificity Structure Testing Therapeutic Therapeutic Uses Thermodynamics Zinc Fingers analog antimicrobial base combinatorial data mining density design enantiomer glucagon-like peptide 1 gramicidin A improved insight macromolecule metal poisoning novel peptide hormone preclinical study programs protein function protein structure public health priorities public health relevance scaffold simulation software development success theories tool toxic metal

项目摘要

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.

描述（由申请人提供）：肽是一种新兴且重要的治疗类别类别，在市场上有40种化合物，在临床或临床前试验中有近700种。在开发肽药物的过程中，氨基酸的d-替代物经常通过降低蛋白水解的易感性来改善药代动力学和药效学特性。通常，通过反复试验或组合方法将这种修饰引入铅化合物中。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。使用蛋白质设计的基本原理，我们将追求具有可变手性能的肽的基于计算，基于结构的开发，从而广泛地扩展了我们创造安全和有效的治疗剂的能力。当前的计算蛋白设计软件的成功归功于数十年来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的设计吗？我们实验室中几种计算设计的杂导蛋白的初步表征表明，Protcad中的工具可扩展到非天然氨基酸。在关注立体化学上不同的肽时，我们将严格测试我们对蛋白质结构和稳定性基本原理的基本理解。我们的具体目的集中于三种合理设计的杂介铅支架，使用了我们实验室开发的Protcad和结构生物信息学工具的组合。每个脚手架都提出了独特的生物物理挑战，探索了分子力和设计中的折叠能量景观的贡献。这些脚手架针对重要的公共卫生优先级，包括：（1）开发有效治疗糖尿病的治疗疗法，（2）为有毒金属中毒提供更安全的分子，以治疗有毒金属中毒，以及（3）提供一种新颖的，理性设计的抗菌药物类。公共卫生相关性：我们正在开发用于基于计算机的肽疗法药物设计的软件。目前，我们将计划集中在公共卫生问题的三个主要领域。第一个是抗糖尿病肽激素，可刺激胰岛素产生并降低血糖。我们还在开发结合有毒金属以促进其从体内的安全清除的肽。最后，我们正在调整来自土壤细菌的天然肽，以产生新的抗生素。肽药物的计算机工程可以为医学和我们对蛋白质功能的基本理解做出很多贡献。