Synthesis and Characterization of Cationic and Cell-penetrating Peptide-based Inhibitors Targeting the NMDA Receptor
Disciplines
Biochemistry
Abstract (300 words maximum)
Alzheimer’s disease (AD) is currently an incurable disease that affects nearly 7 million people in the United States as of 2024, and typically, age groups 65 years and older comprise the majority of those afflicted. This number increases by the year, and the need for treatment options increases with it. Associated with AD are N-methyl-D-aspartate (NMDA) receptors that enable the release of Ca2+ ions from transmembrane ion channels once activated, and the continuous overactivation results in cell death (i.e., neurodegeneration) caused by Ca2+ influx. Memantine is a notable drug treatment option for AD, as it acts as an uncompetitive inhibitor toward NMDA receptors at the GluN1a and GluN2B subunits, blocking from within the transmembrane ion channel. Although memantine reduces Ca2+ influx, neurodegeneration does not completely cease. On the other hand, increasing studies on peptides for therapeutic use against AD have shown that cationic arginine-rich peptides (CARPs) have neuroprotective properties and can even act as antagonists against Ca2+ influx. Cell-penetrating peptides (CPPs) have also been shown to hold some effect over NMDAR inhibition, albeit indirectly through amyloid beta (Aβ) inhibition. With all this taken into consideration, the following peptides were computationally studied for their binding affinities with NMDARs: CN105-CARP (VSRRR), L5a-CPP (RRWQW), R5-CARP (RRRRR), and T2-CPP (LVGVFH). These were synthesized through solid-phase peptide synthesis (SPPS) and cleaved using various cocktails (e.g., Reagent R) depending on the residues present within the peptide. Characterization of these peptides was accomplished through electrospray ionization mass spectroscopy (ESI-MS) to confirm their mass, and in future, the inhibition efficiency of each peptide will be determined using biological assay.
Academic department under which the project should be listed
CSM - Chemistry and Biochemistry
Primary Investigator (PI) Name
Mohammad A. Halim
Synthesis and Characterization of Cationic and Cell-penetrating Peptide-based Inhibitors Targeting the NMDA Receptor
Alzheimer’s disease (AD) is currently an incurable disease that affects nearly 7 million people in the United States as of 2024, and typically, age groups 65 years and older comprise the majority of those afflicted. This number increases by the year, and the need for treatment options increases with it. Associated with AD are N-methyl-D-aspartate (NMDA) receptors that enable the release of Ca2+ ions from transmembrane ion channels once activated, and the continuous overactivation results in cell death (i.e., neurodegeneration) caused by Ca2+ influx. Memantine is a notable drug treatment option for AD, as it acts as an uncompetitive inhibitor toward NMDA receptors at the GluN1a and GluN2B subunits, blocking from within the transmembrane ion channel. Although memantine reduces Ca2+ influx, neurodegeneration does not completely cease. On the other hand, increasing studies on peptides for therapeutic use against AD have shown that cationic arginine-rich peptides (CARPs) have neuroprotective properties and can even act as antagonists against Ca2+ influx. Cell-penetrating peptides (CPPs) have also been shown to hold some effect over NMDAR inhibition, albeit indirectly through amyloid beta (Aβ) inhibition. With all this taken into consideration, the following peptides were computationally studied for their binding affinities with NMDARs: CN105-CARP (VSRRR), L5a-CPP (RRWQW), R5-CARP (RRRRR), and T2-CPP (LVGVFH). These were synthesized through solid-phase peptide synthesis (SPPS) and cleaved using various cocktails (e.g., Reagent R) depending on the residues present within the peptide. Characterization of these peptides was accomplished through electrospray ionization mass spectroscopy (ESI-MS) to confirm their mass, and in future, the inhibition efficiency of each peptide will be determined using biological assay.
