GOALI: Design of Crystal Growth Inhibitors for Kidney Xenostones

技术总结这个项目由固态和材料化学计划支持，联合纽约大学和阿弗瑞特制药公司的研究科学家，研究一系列小分子的晶体生长，这些小分子是作为口服制剂使用的一流的P2X3受体拮抗剂，正被开发为治疗管理不善的慢性疼痛的新疗法，包括癌症、关节炎和内脏疾病引起的疼痛。尽管这些材料显示出很有希望的治疗潜力，但由传入公司进行的动物研究表明，这些化合物在肾脏中被清除，因此集中在尿液中，并可以在肾脏和输尿管中结晶。这些“异种结石”(即异物结石)可能会阻碍尿液从肾脏排出，如果临床上出现这种情况，可能会对患者构成风险。如果需要高剂量才能达到最佳的治疗效果，预计这种不良副作用的可能性会更大。纽约大学-传入研究小组将使用实时原位原子力显微镜在近分子水平上研究这些材料的晶体生长模式，为从大型和结构多样化的传入化合物库中选择晶体生长抑制剂提供必要的信息。这类类似物可以起到“分子模仿者”的作用，通过分子识别结合到选定的晶体生长点，从而阻挡来自这些生长点和周围生长点的磷矿溶质分子的接近。因此，该项目提供了一个独特的机会来充分发展抑制晶体生长的分子冒名顶替原理，并在分子水平上扩大对晶体生长的理解。拟议项目的成果将是一种晶体生长抑制剂，从具有模仿有希望的领先的P2X3受体拮抗剂的分子结构的不同同系物库中挑选出来。被确定为体外最好的抑制剂的化合物将由传入公司通过单独的传入资金来测试它们在体内的有效性。非技术总结这个项目的动机是通过一项研究计划对人类健康产生潜在影响，该计划涵盖了基本的有机固态化学主题，包括固态结构、晶体生长、缺陷和位错，以及纳米级的晶体生长抑制。具体地说，目的是确定晶体生长抑制剂--最终将与活性药物成分(API)一起包括在药物配方中--将减轻上尿路(肾脏和输尿管)中API的结晶，这对患者构成相当大的风险。如果成功，该项目将为治疗管理不善的慢性疼痛提供独特的配方，包括癌症、关节炎和内脏疾病引起的疼痛。该项目取决于纽约大学和艾弗森制药公司的研究人员之间的合作。因此，参与该项目的研究生将受益于对工业部门，特别是制药领域的认识的提高，以及对材料科学在制药中的重要性的日益认识。此外，学生们将享受一个独特的机会，与具有明显社会影响的实际成果捆绑在一起，进行基础研究。纽约大学PI每年夏天都会通过美国化学学会项目种子项目招待一名高中生，每年夏天为经济困难的学生提供研究体验。这个GALI项目将为这些学生提供额外的好处，即进入工业部门的前景。作为纽约大学材料科学和工程中心的主任和泽维尔-纽约大学材料和教育研究伙伴关系的联合PI，PI接待来自少数族裔服务机构的本科生和教职员工进行暑期研究体验，并鼓励这些本科生参与这个项目。国际和平研究所预计将共同组织一次东海岸固体化学研讨会，旨在提高研究生和博士后在科学交流方面的技能和信心，这对他们作为职业科学家的职业发展至关重要。

TECHNICAL SUMMARYThis project, supported by the Solid State and Materials Chemistry program unites research scientists from New York University and Afferent Pharmaceuticals to investigate the crystal growth of a family of small molecules, first in class P2X3 receptor antagonists, administered as an oral formulation, which are being developed as novel treatments for poorly managed chronic pain, including that arising from cancer, arthritis and visceral disorders. Although these materials exhibit promising therapeutic potential, animal studies performed by Afferent have demonstrated that the compounds are renally cleared and thus concentrated in urine, and can crystallize in the kidney and ureter. These "xenostones" (i.e., foreign stones) have potential to obstruct urine egress from the kidney, which if present clinically can pose a risk to patients. The potential for this adverse side effect is expected to be worse in the event that high dosages are required for optimum therapeutic effect. The NYU-Afferent team will employ real-time in situ atomic force microscopy to investigate the crystal growth modes for these materials at the near-molecular level, providing the information necessary for selection of crystal growth inhibitors drawn from a large and structurally diverse library of Afferent compounds. Such analogs could act as "molecular imposters", binding to select crystal growth sites through molecular recognition and thereby blocking the approach of xenostone solute molecules from these and surrounding growth sites. As such, the project provides a unique opportunity to develop fully the molecular imposter principle for crystal growth inhibition and expand understanding of crystal growth at the molecular level. The deliverable of the proposed project will be a crystal growth inhibitor selected from a diverse library of congeners with molecular structures that mimic promising lead P2X3 receptor antagonists. Compounds identified as the best inhibitors in vitro will be tested by Afferent for their in vivo efficacy through separate Afferent funding. NON-TECHNICAL SUMMARYThe motivation for this project is driven by its potential impact on human health through a research plan that encompasses fundamental organic solid-state chemistry subjects, including solid-state structure, crystal growth, defects and dislocations, and crystal growth inhibition at the nanoscale. Specifically, the aim is to identify crystal growth inhibitors - to be included eventually in pharmaceutical formulations along with an active pharmaceutical ingredient (API) - that will mitigate crystallization of the API in the upper urinary tract (kidney and ureter), which poses a considerable risk to patients. If successful, the project will provide unique formulations for poorly managed chronic pain, including that arising from cancer, arthritis and visceral disorders. The project hinges on a collaboration between investigators from New York University and Afferent Pharmaceuticals. As such, graduate students involved in the project will benefit from increased awareness of the industrial sector, particularly the pharmaceutical arena, and of the increasing recognition of the importance of materials science in pharmaceuticals. Moreover, students will enjoy a unique opportunity to pursue fundamental research tethered to a practical outcome with clear societal impact. The NYU PI has been hosting a high school student each summer through the American Chemical Society Project SEED program, providing a research experience for an economically disadvantaged student each summer. This GOALI project will provide such students with an additional benefit, namely a view into the industrial sector. As Director of the NYU Materials Science and Engineering Center and a co-PI on the Xavier-NYU Partnership for Research in Materials and Education, the PI hosts undergraduates and faculty from minority-serving institutions for summer research experiences, and the participation of these undergraduates in this project also will be encouraged. The PI anticipates co-organizing an East Coast Solid State Chemistry Symposium designed to elevate skills and confidence among graduate students and postdocs in scientific communication, which is essential for their professional development as career scientists.