Antimicrobial Peptides Inhibitors for Main Protease of SARS-CoV-2

Disciplines

Biochemistry | Immunology and Infectious Disease

Abstract (300 words maximum)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) still poses a significant risk to people’s health with 774 million infections and 7 million deaths as of March 2024. SARS-CoV-2 is a positive-sense single stranded RNA virus consisting of 29 proteins. The main protease (Mpro) of SARS-CoV-2 has been identified to play a crucial role in viral replication and transcription. Ideally, inhibition of the Mpro would prevent replication and allow us to effectively prevent and treat SARS-CoV-2. Peptides therapeutics have been utilized in the inhibition of the Mpro due to their targeted binding ability to the catalytic dyad His41 and Cys145. In this study, we synthesized three antimicrobial peptides including DRAMP01613, DRAMP02397, and DRAMP03064 to inhibit the Mpro. These peptides are non-cytotoxic with strong antimicrobial properties and were chosen because of their higher binding affinity as evident from our previous bioinformatics studies. The DRAMP peptides were synthesized using a CEM Liberty Blue peptide synthesizer with automated Fmoc solid phase synthesis protocols and cleaved using a 95% trifluoracetic acid mixture. The peptides were then precipitated with diethyl ether and subsequently lyophilized. All peptides theoretical masses were confirmed through mass spectrometry and then stored in 4° C. To measure the 50% inhibitory concentration (IC50) value of these peptides, a selected ion monitoring (SIM) based LCMS (liquid chromatography coupled with mass spectrometry) assay was conducted. DRAMP03064 demonstrated the highest inhibition efficiency with an IC50 value of 378 nanomolar (nM) whereas the DRAMP02397 showed the moderate inhibition efficiency (IC50 5.72 micromolar).

Academic department under which the project should be listed

CSM - Chemistry and Biochemistry

Primary Investigator (PI) Name

Mohammad A. Halim

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Antimicrobial Peptides Inhibitors for Main Protease of SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) still poses a significant risk to people’s health with 774 million infections and 7 million deaths as of March 2024. SARS-CoV-2 is a positive-sense single stranded RNA virus consisting of 29 proteins. The main protease (Mpro) of SARS-CoV-2 has been identified to play a crucial role in viral replication and transcription. Ideally, inhibition of the Mpro would prevent replication and allow us to effectively prevent and treat SARS-CoV-2. Peptides therapeutics have been utilized in the inhibition of the Mpro due to their targeted binding ability to the catalytic dyad His41 and Cys145. In this study, we synthesized three antimicrobial peptides including DRAMP01613, DRAMP02397, and DRAMP03064 to inhibit the Mpro. These peptides are non-cytotoxic with strong antimicrobial properties and were chosen because of their higher binding affinity as evident from our previous bioinformatics studies. The DRAMP peptides were synthesized using a CEM Liberty Blue peptide synthesizer with automated Fmoc solid phase synthesis protocols and cleaved using a 95% trifluoracetic acid mixture. The peptides were then precipitated with diethyl ether and subsequently lyophilized. All peptides theoretical masses were confirmed through mass spectrometry and then stored in 4° C. To measure the 50% inhibitory concentration (IC50) value of these peptides, a selected ion monitoring (SIM) based LCMS (liquid chromatography coupled with mass spectrometry) assay was conducted. DRAMP03064 demonstrated the highest inhibition efficiency with an IC50 value of 378 nanomolar (nM) whereas the DRAMP02397 showed the moderate inhibition efficiency (IC50 5.72 micromolar).