Development and Characterization of Small Molecule Activators of Peptidase Neurolysin for Stroke Therapy

Oakland University, Rochester MI

Investigators

Linked publications, trials & patents

Abstract

SUMMARY Current stroke research focuses more on understanding the brain’s self-protective and repair mechanisms. Detailed elucidation of these mechanisms is crucial as such knowledge could lead to development of therapeutic interventions which mimic or engage the brain’s self-protective/repair mechanisms and can lead to successful stroke therapy. With the proposed research we seek to develop potent and selective ‘drug-like’ small molecule activators of peptidase neurolysin (Nln) which will be used as research tools and lead chemical entities to address the critical unmet need for stroke treatments. Our recently published and pilot studies have identified Nln as a leading brain self-protective mechanism, functioning towards cerbroprotection and recovery after stroke. Functional significance of Nln in the post-stroke brain is based on its ability to inactivate several neurotoxic peptides and generate three cerebro-protective/regenerative peptides, which are known from numerous experimental and clinical studies to critically contribute to the outcome of stroke. Based on this evidence we view Nln as a central peptidase involved in protection of the brain following stroke. In this collaborative renewal application, we will leverage our expertise in multiple aspects of the drug discovery process to further optimize lead molecules of two distinct chemotypes, developed during the first cycle of this R01 grant, to improve their potency and ‘drug-like’ properties for selective activation of Nln as experimental therapeutic agents for cerebroprotection after ischemic stroke. This proposal has been formulated based on our compelling experimental data revealing the discovery of two diverse Nln activator chemotypes that bind to Nln and enhance its catalytic activity; extensive structure-activity relationship, hit-to-lead optimization and pharmacokinetic studies; and initial in vivo proof-of-concept efficacy studies, in two mouse models of ischemic stroke, demonstrating the cerebroprotective effects of a lead Nln activator. The goals of this proposal will be accomplished in three well-integrated aims: (1) conduct lead optimization to further refine activity and ‘drug-like’ properties of Nln activators; (2) perform biochemical and structural studies to characterize the activation mechanism that the identified Nln activators exploit; (3) determine the therapeutic potential of Nln activators in post-stroke cerebroprotection using two mouse models of ischemic stroke. This work is highly innovative because our multi-mechanism molecules are the first and only Nln activators described in the scientific and patent literature, and the therapeutic potential of such compounds has not been recognized before. The collaborative investigative team, comprising experts in medicinal chemistry and drug discovery, cryo-EM and structural biology, enzyme biochemistry and pharmacology, blood-brain barrier physiology and stroke pharmacology, is highly qualified to conduct the proposed studies. Our long-term goal is to translate the lead Nln activators from bench to bedside and develop an effective stroke therapy, which will transform the current treatment modalities for a vast number of stroke patients.