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A general chemical principle for creating closure-stabilizing integrin inhibitors.

ABSTRACT: Integrins are validated drug targets with six approved therapeutics. However, small-molecule inhibitors to three integrins failed in late-stage clinical trials for chronic indications. Such unfavorable outcomes may in part be caused by partial agonism, i.e., the stabilization of the high-affinity, extended-open integrin conformation. Here, we show that the failed, small-molecule inhibitors of integrins αIIbβ3 and α4β1 stabilize the high-affinity conformation. Furthermore, we discovered a simple chemical feature present in multiple αIIbβ3 antagonists that stabilizes integrins in their bent-closed conformation. Closing inhibitors contain a polar nitrogen atom that stabilizes, via hydrogen bonds, a water molecule that intervenes between a serine residue and the metal in the metal-ion-dependent adhesion site (MIDAS). Expulsion of this water is a requisite for transition to the open conformation. This change in metal coordination is general to integrins, suggesting broad applicability of the drug-design principle to the integrin family, as validated with a distantly related integrin, α4β1.

SUBMITTER: Lin FY

PROVIDER: S-EPMC9494814 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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A general chemical principle for creating closure-stabilizing integrin inhibitors.

Lin Fu-Yang FY Li Jing J Xie Yonghua Y Zhu Jianghai J Huong Nguyen Thi Thu TT Zhang Yonghui Y Zhu Jieqing J Springer Timothy A TA

Cell 20220901 19

Integrins are validated drug targets with six approved therapeutics. However, small-molecule inhibitors to three integrins failed in late-stage clinical trials for chronic indications. Such unfavorable outcomes may in part be caused by partial agonism, i.e., the stabilization of the high-affinity, extended-open integrin conformation. Here, we show that the failed, small-molecule inhibitors of integrins αIIbβ3 and α4β1 stabilize the high-affinity conformation. Furthermore, we discovered a simple ...[more]

PMID: 36113427

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Project description:The development of new biological and chemical instruments for research and diagnostic applications is often slowed by the cost, specialization, and custom nature of these instruments. New instruments are built from components that are drawn from a host of different disciplines and not designed to integrate together, and once built, an instrument typically performs a limited number of tasks and cannot be easily adapted for new applications. Consequently, the process of inventing new instruments is very inefficient, especially for researchers or clinicians in resource-limited settings. To improve this situation, we propose that a family of standardized multidisciplinary components is needed, a set of "building blocks" that perform a wide array of different tasks and are designed to integrate together. Using these components, scientists, engineers, and clinicians would be able to build custom instruments for their own unique needs quickly and easily. In this work we present the foundation of this set of components, a system we call Multifluidic Evolutionary Components (MECs). "Multifluidic" conveys the wide range of fluid volumes MECs operate upon (from nanoliters to milliliters and beyond); "multi" also reflects the multiple disciplines supported by the system (not only fluidics but also electronics, optics, and mechanics). "Evolutionary" refers to the design principles that enable the library of MEC parts to easily grow and adapt to new applications. Each MEC "building block" performs a fundamental function that is commonly found in biological or chemical instruments, functions like valving, pumping, mixing, controlling, and sensing. Each MEC also has a unique symbol linked to a physical definition, which enables instruments to be designed rapidly and efficiently using schematics. As a proof-of-concept, we use MECs to build a variety of instruments, including a fluidic routing and mixing system capable of manipulating fluid volumes over five orders of magnitude, an acid-base titration instrument suitable for use in schools, and a bioreactor suitable for maintaining and analyzing cell cultures in research and diagnostic applications. These are the first of many instruments that can be built by researchers, clinicians, and students using the MEC system.

Dataset Information

A general chemical principle for creating closure-stabilizing integrin inhibitors.

Publications

A general chemical principle for creating closure-stabilizing integrin inhibitors.

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