The Inhibition of Acetylcholinesterase by Spider Venom Peptides to Treat Alzheimer's Disease
Disciplines
Biochemistry | Medicinal-Pharmaceutical Chemistry
Abstract (300 words maximum)
Alzheimer's disease (AD) is one of the leading neurodegenerative disorders evident by a decline in cognition and memory. According to the NIH, Alzheimer’s affects over 6.5 million people across the United States yearly and by 2060 this number could double. The biggest component to Alzheimer's disease is the buildup of plaque that will accumulate between neurons and cause their degradation. This can prevent new memories from being formed and cause the loss of neurons in the prefrontal cortex of the brain which is responsible for complex thinking as well as working memory. Acetylcholinesterase (AChE) is an enzyme that breaks down and regulates the amount of acetylcholine (ACh) released in the brain. Acetylcholine acts as a neurotransmitter that is released in the brain and at the neuromuscular junction making it responsible for memory function. Patients with AD have a reduced amount of acetylcholine (ACh) within their brain and inhibiting the Acetylcholinesterase will increase the amount of ACh. Some studies showed that venom peptides can inhibit the Acetylcholinesterase, however, no studies are conducted to test the inhibition efficiency of the spider venom peptides. In this study, we collected over 25 spider venom peptides and tested their binding affinity and interaction with Acetylcholinesterase by molecular docking. Among these peptides, 5 peptides (BP0506-VTX, BP0424-1LUP, BP0518-1QK7, BP0653-1LU8, BP0682-2N1N) showed the highest binding affinity. Molecular docking was performed using HDOCK tool. Based on the computational results, BP0506-VTX demonstrated the highest binding affinities with a score of (-277.93) followed by BP0424-1LUP (-249.29), BP0518-1QK7 (-235.24), BP0653-1LU8 (-228.72), and BP0682-2N1N (-228.36). The best peptide BP0506-VTX was synthesized with an acetylated N-terminus and amidated C-terminus on a Liberty Blue microwave peptide synthesizer (CEM). The synthesized peptide was characterized by Agilent UPLC coupled with LTQ XL mass spectrometer. These results can accelerate the rational design of selective spider peptide inhibitors targeting the AChE.
Academic department under which the project should be listed
Chemistry and Biochemistry
Primary Investigator (PI) Name
Mohammad A. Halim
The Inhibition of Acetylcholinesterase by Spider Venom Peptides to Treat Alzheimer's Disease
Alzheimer's disease (AD) is one of the leading neurodegenerative disorders evident by a decline in cognition and memory. According to the NIH, Alzheimer’s affects over 6.5 million people across the United States yearly and by 2060 this number could double. The biggest component to Alzheimer's disease is the buildup of plaque that will accumulate between neurons and cause their degradation. This can prevent new memories from being formed and cause the loss of neurons in the prefrontal cortex of the brain which is responsible for complex thinking as well as working memory. Acetylcholinesterase (AChE) is an enzyme that breaks down and regulates the amount of acetylcholine (ACh) released in the brain. Acetylcholine acts as a neurotransmitter that is released in the brain and at the neuromuscular junction making it responsible for memory function. Patients with AD have a reduced amount of acetylcholine (ACh) within their brain and inhibiting the Acetylcholinesterase will increase the amount of ACh. Some studies showed that venom peptides can inhibit the Acetylcholinesterase, however, no studies are conducted to test the inhibition efficiency of the spider venom peptides. In this study, we collected over 25 spider venom peptides and tested their binding affinity and interaction with Acetylcholinesterase by molecular docking. Among these peptides, 5 peptides (BP0506-VTX, BP0424-1LUP, BP0518-1QK7, BP0653-1LU8, BP0682-2N1N) showed the highest binding affinity. Molecular docking was performed using HDOCK tool. Based on the computational results, BP0506-VTX demonstrated the highest binding affinities with a score of (-277.93) followed by BP0424-1LUP (-249.29), BP0518-1QK7 (-235.24), BP0653-1LU8 (-228.72), and BP0682-2N1N (-228.36). The best peptide BP0506-VTX was synthesized with an acetylated N-terminus and amidated C-terminus on a Liberty Blue microwave peptide synthesizer (CEM). The synthesized peptide was characterized by Agilent UPLC coupled with LTQ XL mass spectrometer. These results can accelerate the rational design of selective spider peptide inhibitors targeting the AChE.