Development of Matrix Metalloproteinase Inhibitors for Stroke

Matrix metalloproteinases (MMPs) are a conserved family of zinc-dependent proteases that degrade all components of the extracellular matrix (ECM). At least 23 MMPs are currently known to be capable of degrading a range of ECM components and processing a variety of bioactive molecules. Enhanced expression and activity of MMPs have been observed in numerous pathological conditions, including ischemic stroke. Specifically, MMP-mediated alterations lead to BBB leakage, cerebral edema, hemorrhage, leukocyte infiltration, and progressive inflammatory reactions, contributing to brain tissue loss. Therefore, MMPs are among of the most important therapeutic targets in ischemic stroke.

Fig. 1. Activation of matrix metalloproteinases and blood-brain barrier disruption after ischemic stroke. Fig. 1 Activation of MMPs and blood-brain barrier (BBB) disruption after ischemic stroke. (Veeravalli, 2024)

Our Matrix Metalloproteinase Inhibitor Development Services

As a global stroke research service provider, Ace Therapeutics provides end-to-end solutions for novel MMP inhibitor discovery and development. Our team of scientists, with expertise in MMP biology and medicinal chemistry, specializes in the design and development of MMP inhibitors across multiple modalities, including small molecules, monoclonal antibodies, and protein-engineered inhibitors.

We offer full-spectrum services, from target identification and validation through lead optimization to preclinical evaluation studies, leveraging our advanced technologies and reliable drug discovery platform to accelerate the development of novel stroke therapeutics.

Services	Service Details
Target identification and validation	Identify and validate MMP targets relevant to stroke using advanced molecular and cellular biology technologies.
Drug design and synthesis	Design MMP inhibitors targeting the catalytic domain of MMP, rather than the Zn binding site. Synthesize MMP inhibitors that function by inhibiting non-catalytic domains, such as the hemopexin domain, the collagen binding domain, and the pro-peptide domain.
Pharmacodynamic studies	Evaluate the neuroprotective effects, blood-brain barrier protection, and improvement of neurological deficits of MMP inhibitors in animal models of stroke.
Pharmacokinetic studies	Assess the absorption, distribution, metabolism, and excretion (ADME) properties of MMP inhibitors.
Safety assessment	Provide comprehensive toxicology studies to evaluate the safety profile of MMP inhibitors.

Types of MMP Inhibitors We Can Development

Service	Service Details
Development of MMP-9 inhibitors for stroke	Identify highly selective compounds that inhibit the activation of MMP-9 zymogen and subsequent generation of catalytically active enzyme while minimizing off-target effects on other MMPs, e.g., MMP-1, -2, -3, and -14, through biochemical and structural screening. Assess activity of MMP-9 inhibitors using zymography, reverse zymography, and gelatinase assay. Develop biotherapeutic approaches to inhibit MMP-9, such as MMP-9 neutralizing antibodies, MMP-9 siRNAs, and MMP-9 shRNAs delivered through adenoviral vectors, lentiviral vectors, quantum dots, and gold nanoparticles. Develop new chemical entities that can inhibit MMP-9.
Development of hydroxamic acid-based MMP inhibitors for stroke	Design small molecules featuring a hydroxamic acid group strategically positioned for optimal interaction with the catalytic zinc ion Develop synthetic routes for incorporating the hydroxamic acid group into the molecular scaffold. Optimize the molecular scaffold for improved binding affinity, selectivity, and pharmacokinetic properties.
Development of mechanism-based MMP inhibitors for stroke	Employ computational tools to design inhibitors selectively targeting MMP-2 and MMP-9. Synthesize small molecules or peptidomimetics targeting the active or allosteric sites of MMP-2 and MMP-9.

Ace Therapeutics provides specialized research and development services to support global partners in advancing MMP inhibitors for stroke. Contact us to learn more about our expertise and collaboration opportunities.

Reference

Veeravalli, K. K. (2024). Implications of MMP-12 in the pathophysiology of ischemic stroke. Stroke and Vascular Neurology, 9(2).

All of our services are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.