Synthesis and Characterization of Snails Venom Peptide as a Potential Inhibitor of NMDA Receptors in Alzheimer’s Disease
Disciplines
Analytical Chemistry | Biochemistry | Computational Chemistry | Medicinal-Pharmaceutical Chemistry
Abstract (300 words maximum)
Alzheimer’s Disease (AD) is a neurodegenerative disease which is affecting million people globally. In 2021, 6.5 million people in US alone spent billions dollar for their treatment. While there is no cure for AD yet, there are therapeutics in development to slow the progression of AD. The specific aspect of AD which this study focuses on is the inhibition of the N-methyl-D-aspartate (NMDA) receptor. Previous research has shown that, in AD patients, the overactivation of the NMDA receptor leads to an overabundance of Ca+ ions within the nerve cell. This activates digestive enzymes causing premature neuron death which leads to dementia. Memantine has seen use in inhibiting NMDA which slowed the onset of dementia in AD patients. Additionally, cone snails venom peptides have shown potential in blocking the flow of ions through NMDA. In this study, computational screening of 41 Conus venom peptide against NMDA was conducted. Several peptides exhibited strong binding affinity with NMDA. Two peptides, 1M2C and 2I28, showed the binding affinity of -53.52 and -47.95 kcal/mol, respectively. These peptide candidates were synthesized using the standard Fmoc synthesis protocols by CEM Liberty Blue peptide synthesizer. Peptides’ characterizations were then conducted by mass spectrometry. The linear peptide showed two strong peaks at m/z 858.83 and 1715.17 correspond to [M+2H]2+ and [M+H]+ ions, respectively which exactly matched with the theoretical values. Cyclic peptide was synthesized by adding 10% DMSO and stirred for 24-48 hours. Cyclization was confirmed by mass spectrometry which showed the removal of four hydrogen (mass shift by 4) from four cysteine residues and forming disulfide bonds between Cys2-Cys8 and Cys3-Cys16. The performance of these peptides will be evaluated with Alzheimer animal model. The obtained results can accelerate the rational design of snails’ venom peptide inhibitors in the development of Alzheimer’s Disease therapeutics.
Academic department under which the project should be listed
CSM - Chemistry and Biochemistry
Primary Investigator (PI) Name
Mohammad A. Halim
Synthesis and Characterization of Snails Venom Peptide as a Potential Inhibitor of NMDA Receptors in Alzheimer’s Disease
Alzheimer’s Disease (AD) is a neurodegenerative disease which is affecting million people globally. In 2021, 6.5 million people in US alone spent billions dollar for their treatment. While there is no cure for AD yet, there are therapeutics in development to slow the progression of AD. The specific aspect of AD which this study focuses on is the inhibition of the N-methyl-D-aspartate (NMDA) receptor. Previous research has shown that, in AD patients, the overactivation of the NMDA receptor leads to an overabundance of Ca+ ions within the nerve cell. This activates digestive enzymes causing premature neuron death which leads to dementia. Memantine has seen use in inhibiting NMDA which slowed the onset of dementia in AD patients. Additionally, cone snails venom peptides have shown potential in blocking the flow of ions through NMDA. In this study, computational screening of 41 Conus venom peptide against NMDA was conducted. Several peptides exhibited strong binding affinity with NMDA. Two peptides, 1M2C and 2I28, showed the binding affinity of -53.52 and -47.95 kcal/mol, respectively. These peptide candidates were synthesized using the standard Fmoc synthesis protocols by CEM Liberty Blue peptide synthesizer. Peptides’ characterizations were then conducted by mass spectrometry. The linear peptide showed two strong peaks at m/z 858.83 and 1715.17 correspond to [M+2H]2+ and [M+H]+ ions, respectively which exactly matched with the theoretical values. Cyclic peptide was synthesized by adding 10% DMSO and stirred for 24-48 hours. Cyclization was confirmed by mass spectrometry which showed the removal of four hydrogen (mass shift by 4) from four cysteine residues and forming disulfide bonds between Cys2-Cys8 and Cys3-Cys16. The performance of these peptides will be evaluated with Alzheimer animal model. The obtained results can accelerate the rational design of snails’ venom peptide inhibitors in the development of Alzheimer’s Disease therapeutics.