GOALI: Design of Crystal Growth Inhibitors for Kidney Xenostones

技术概述该项目由固态和材料化学计划支持，联合了来自纽约大学和Afferent Pharmaceuticals的研究科学家，以研究一系列小分子的晶体生长，首先是作为口服制剂给药的P2 X3受体拮抗剂，其正在开发作为管理不善的慢性疼痛的新治疗方法，包括癌症引起的疼痛，关节炎和内脏疾病。虽然这些材料显示出有希望的治疗潜力，但由Afferent进行的动物研究表明，这些化合物经肾脏清除，因此浓缩在尿液中，并可在肾脏和输尿管中结晶。这些“异源石”（即，外来结石）有可能阻碍尿液从肾脏排出，如果临床上存在的话，可能对患者造成危险。在需要高剂量以获得最佳治疗效果的情况下，预计这种不良副作用的可能性会更糟。纽约大学-传入团队将采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，为从大量结构多样的传入化合物库中选择晶体生长抑制剂提供必要的信息。 这样的类似物可以充当“分子冒名顶替者”，通过分子识别结合到选择的晶体生长位点，从而阻断异源石溶质分子从这些和周围生长位点的接近。因此，该项目提供了一个独特的机会，以充分发展晶体生长抑制的分子冒名顶替者原则，并在分子水平上扩大对晶体生长的理解。拟议项目的可交付成果将是一种晶体生长抑制剂，该抑制剂选自具有模拟有前途的先导P2 X3受体拮抗剂的分子结构的各种同系物库。在体外被确定为最佳抑制剂的化合物将由Afferent通过单独的Afferent资金对其体内功效进行测试。非技术性总结本项目的动机是通过一项研究计划对人类健康的潜在影响，该研究计划包括基本的有机固态化学学科，包括固态结构，晶体生长，缺陷和位错，以及纳米级晶体生长抑制。具体而言，目的是确定晶体生长抑制剂-最终与活性药物成分（API）一起沿着包含在药物制剂中-这将减轻API在上尿路（肾脏和输尿管）中的结晶，这对患者构成相当大的风险。如果成功，该项目将为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Afferent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，特别是制药竞技场的认识的提高，以及对材料科学在制药中的重要性的认识的提高。此外，学生将享受一个独特的机会，追求基础研究拴到一个具有明确的社会影响的实际成果。纽约大学PI每年夏天都通过美国化学学会项目种子计划接待一名高中生，每年夏天为一名经济困难的学生提供研究经验。这个GOALI项目将为这些学生提供额外的好处，即进入工业部门的观点。作为纽约大学材料科学与工程中心的主任，以及泽维尔-纽约大学材料与教育研究合作伙伴关系的共同PI，PI接待来自少数民族服务机构的本科生和教师进行夏季研究体验，并鼓励这些本科生参与该项目。PI预计将共同组织一个东海岸固态化学研讨会，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专业发展至关重要。

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.