Design and Synthesis of Histidine-rich Peptides Analogs Targeting 3-Chemotrypsin Like Protease of SARS-CoV-2
Disciplines
Biochemistry | Medicinal-Pharmaceutical Chemistry
Abstract (300 words maximum)
Since the development of COVID-19, a disease caused by SARS-CoV-2, there has been a need for the development of an innovative solution to increase the bioavailability of inhibitors of SARS-CoV-2. COVID-19 has decreased the global life expectancy by 1.6 years from 2019-2020. Peptide therapeutics are effective because of their high affinity with receptors and low toxicity compared to small molecule drugs. Additionally, they can reduce off-target side effects because of their heightened target specificity and potency. The aim of this research is to design, model and synthesize the peptide that had the highest binding affinity and would be most effective when inhibiting the SARS-CoV-2 main protease (Mpro). The 3CLpro protein of SARS-CoV-2 was targeted because it is essential for viral processing of SARS-CoV-2. Ten (10) new analogues containing several histidine amino acids were designed based on a peptide which showed inhibition efficiency against the Mpro. Peptides were modeled in Alpha-Fold to obtain the 3D structures and were then processed through the HDOCK server for molecular docking. The peptide analog 9 with the strongest binding affinity was analyzed and prepared for synthesis using the solid phase synthesis protocol employing a high swelling rink amide resin. After the peptide synthesis, the bond between peptide-resin complex was cleaved with 95% TFA, 2.5% H2O, and 2.5% Triisopropylsilane. The cleaved peptides were filtered, precipitated by adding cold ether, and lyophilized using acetic acid. The mass spectrometry experiment was conducted by dissolving peptide in 50%:49%:1% acetonitrile: water: formic acid solution at a concentration of 50 micromolar. Three intense peaks were detected at m/z 428.58, 642.33, and 1283.58 which correspond to the charge states of the peptide. However, one of the glycine is noticed to cleave from peptide as well. After synthesizing the peptide correctly, the analog 9 will be tested for inhibition efficiency using protease assays.
Academic department under which the project should be listed
CSM - Chemistry and Biochemistry
Primary Investigator (PI) Name
Mohammad Halim
Design and Synthesis of Histidine-rich Peptides Analogs Targeting 3-Chemotrypsin Like Protease of SARS-CoV-2
Since the development of COVID-19, a disease caused by SARS-CoV-2, there has been a need for the development of an innovative solution to increase the bioavailability of inhibitors of SARS-CoV-2. COVID-19 has decreased the global life expectancy by 1.6 years from 2019-2020. Peptide therapeutics are effective because of their high affinity with receptors and low toxicity compared to small molecule drugs. Additionally, they can reduce off-target side effects because of their heightened target specificity and potency. The aim of this research is to design, model and synthesize the peptide that had the highest binding affinity and would be most effective when inhibiting the SARS-CoV-2 main protease (Mpro). The 3CLpro protein of SARS-CoV-2 was targeted because it is essential for viral processing of SARS-CoV-2. Ten (10) new analogues containing several histidine amino acids were designed based on a peptide which showed inhibition efficiency against the Mpro. Peptides were modeled in Alpha-Fold to obtain the 3D structures and were then processed through the HDOCK server for molecular docking. The peptide analog 9 with the strongest binding affinity was analyzed and prepared for synthesis using the solid phase synthesis protocol employing a high swelling rink amide resin. After the peptide synthesis, the bond between peptide-resin complex was cleaved with 95% TFA, 2.5% H2O, and 2.5% Triisopropylsilane. The cleaved peptides were filtered, precipitated by adding cold ether, and lyophilized using acetic acid. The mass spectrometry experiment was conducted by dissolving peptide in 50%:49%:1% acetonitrile: water: formic acid solution at a concentration of 50 micromolar. Three intense peaks were detected at m/z 428.58, 642.33, and 1283.58 which correspond to the charge states of the peptide. However, one of the glycine is noticed to cleave from peptide as well. After synthesizing the peptide correctly, the analog 9 will be tested for inhibition efficiency using protease assays.