PSD-95 Inhibitor Development for Stroke

There is increasing evidence that excitotoxic neuronal damage associated with glutamate release plays a key role in the pathogenesis of focal cerebral ischemia. Since direct inhibition of glutamate receptors has shown limited success, a new strategy focuses on modulating the intracellular signaling pathways that link the activation of these receptors to excitotoxic mediators. The postsynaptic density-95 (PSD-95) scaffold protein promotes the binding of N-methyl-D-aspartic acid receptors (NMDARs) to other proteins and is central to glutamatergic synaptic signaling. Inhibition of PSD-95 proteins can prevent harmful effects such as nitric oxide production and calcium influx, while maintaining normal NMDAR function. Compounds with this mechanism of action are being investigated as potential neuroprotective agents for stroke.

Fig. 1. A paradigm for understanding how PSD-95 is regulated during excitotoxic events and the impact of peptides specifically targeting PSD-95. Fig. 1 Model of PSD-95 regulation in excitotoxicity and action of PSD-95-targeted peptides. (Ugalde-Triviño, et al., 2021)

Our PSD-95 Inhibitor Development Services

At Ace Therapeutics, we have advanced imaging technology, reliable in vitro and in vivo models of stroke, and a team of experienced scientists to accelerate the discovery and optimization of PSD-95 inhibitors. Our comprehensive services include target validation, high-throughput screening, lead optimization, pharmacokinetic and pharmacodynamic studies, and efficacy testing in animal models of stroke.

Development of peptides that dissociate the GluN2B-PSD-95-nNOS complexes for stroke

Services	Service Details
Development of peptides targeting GluN2B-PSD-95-nNOS complexes	Peptide design: Design peptides targeting the GluN2B-PSD-95-nNOS complex that reduce neurotoxic signaling while maintaining normal NMDAR function. Safety and efficacy testing: Evaluate the safety and efficacy of these peptides in animal models of stroke.
Development of dimeric peptides targeting the PDZ domains of PSD-95	We help clients develop high-affinity dimeric peptides targeting the PDZ domains of PSD-95 against stroke. Peptide design and optimization: Generate dimeric peptide structures with enhanced affinity and selectivity using innovative strategies such as PEG cross-linking for improved stability and BBB permeability. Assessment of peptide structure and function: Analyze peptide conformations and interactions by cutting-edge techniques such as nuclear magnetic resonance (NMR) and small angle X-ray scattering (SAXS). Stability and efficacy testing: Provide comprehensive plasma stability and efficacy testing to validate the therapeutic potential of dimeric peptides in preclinical stroke models.

Services

Service Details

Development of peptides targeting GluN2B-PSD-95-nNOS complexes

Peptide design: Design peptides targeting the GluN2B-PSD-95-nNOS complex that reduce neurotoxic signaling while maintaining normal NMDAR function.
Safety and efficacy testing: Evaluate the safety and efficacy of these peptides in animal models of stroke.

Development of dimeric peptides targeting the PDZ domains of PSD-95

We help clients develop high-affinity dimeric peptides targeting the PDZ domains of PSD-95 against stroke.

Peptide design and optimization: Generate dimeric peptide structures with enhanced affinity and selectivity using innovative strategies such as PEG cross-linking for improved stability and BBB permeability.
Assessment of peptide structure and function: Analyze peptide conformations and interactions by cutting-edge techniques such as nuclear magnetic resonance (NMR) and small angle X-ray scattering (SAXS).
Stability and efficacy testing: Provide comprehensive plasma stability and efficacy testing to validate the therapeutic potential of dimeric peptides in preclinical stroke models.

Development of PSD-95 targeted cell-penetrating peptides for stroke

Service	Service Details
Development of neuroprotective peptides for preventing PSD-95 processing	We help our clients develop stroke therapies that target PSD-95 by preventing the characteristic processing of this protein induced by NMDAR overactivation. Peptide design: Combine biochemical analysis, in silico studies, and fragment purification and sequencing to help clients design Tat-based cell-penetrating peptides that can selectively target the PSD-95 calpain cleavage sequences. Preclinical testing: Provide comprehensive preclinical evaluation services in animal models of stroke to assess the ability of peptides to cross the BBB, measure efficacy in reducing infarct volume, and improve neurological outcomes.

Service

Service Details

Development of neuroprotective peptides for preventing PSD-95 processing

We help our clients develop stroke therapies that target PSD-95 by preventing the characteristic processing of this protein induced by NMDAR overactivation.

Peptide design: Combine biochemical analysis, in silico studies, and fragment purification and sequencing to help clients design Tat-based cell-penetrating peptides that can selectively target the PSD-95 calpain cleavage sequences.
Preclinical testing: Provide comprehensive preclinical evaluation services in animal models of stroke to assess the ability of peptides to cross the BBB, measure efficacy in reducing infarct volume, and improve neurological outcomes.

Ace Therapeutics specializes in assisting clients with the design, optimization, and validation of innovative PSD-95 inhibitors. We leverage advanced technologies and our extensive expertise in neuropharmacology to deliver exceptional results. If you are interested in our services, please contact us for more information.

Reference

Ugalde-Triviño, L., & Díaz-Guerra, M. (2021). PSD-95: an effective target for stroke therapy using neuroprotective peptides. International Journal of Molecular Sciences, 22(22), 12585.

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