GOALI: Design of Crystal Growth Inhibitors for Kidney Xenostones

New York University, New York NY

Investigators

Abstract

TECHNICAL SUMMARY This 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 SUMMARY The 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.