Peptide-based Drug Development to Stop the Viral Replication of SARS-CoV-2

Disciplines

Biochemistry | Medicinal-Pharmaceutical Chemistry

Abstract (300 words maximum)

Almost all the antiviral medications we use today are small molecule drug. Several small molecules drugs have showed promising results for covid-19 treatment and a Pfizer (PF-07321332) drug is approved for emergency use. However, small molecule drugs often induce harmful off-target effects and lead to therapy resistance on prolonged use. Peptides are comprised of amino acids; however, they have few amino acids (2-50) compared to proteins. Peptide can be used as a drug (such as Insulin, a peptide hormone, is used to treat diabetics) for various diseases but not yet developed for Covid treatment. Peptide-based therapeutics are very attractive over small-molecule medications, as they are highly selective, well-tolerated, and have less adverse effects. In this research, we have developed peptide-based drug targeting the main protease of SARS-CoV-2 which performs a very critical function in viral replication. The initial lead peptide (Temporin L, TL) was identified based on computational screening. The FRET and selected ion monitoring (SIM) based assays showed an estimated IC50 of TL at 38.80 and 23.8 μM, respectively against the 3CLpro of SARS-CoV-2. Numerous staple and dimer peptides analogues were designed, synthesized, and tested their biological efficiency. The in-vitro investigation revealed that several analogues showed improved inhibition efficiency and the best α-methylated staple (TLP3M3) peptide demonstrated an estimated IC50 at 284 nanomolar (nM) and outstanding (~8h) serum stability. This study showed that the best peptide candidate will further be improved through structural-based rational design for Covid treatment.

Academic department under which the project should be listed

CSM - Chemistry and Biochemistry

Primary Investigator (PI) Name

Mohammad A. Halim

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Peptide-based Drug Development to Stop the Viral Replication of SARS-CoV-2

Almost all the antiviral medications we use today are small molecule drug. Several small molecules drugs have showed promising results for covid-19 treatment and a Pfizer (PF-07321332) drug is approved for emergency use. However, small molecule drugs often induce harmful off-target effects and lead to therapy resistance on prolonged use. Peptides are comprised of amino acids; however, they have few amino acids (2-50) compared to proteins. Peptide can be used as a drug (such as Insulin, a peptide hormone, is used to treat diabetics) for various diseases but not yet developed for Covid treatment. Peptide-based therapeutics are very attractive over small-molecule medications, as they are highly selective, well-tolerated, and have less adverse effects. In this research, we have developed peptide-based drug targeting the main protease of SARS-CoV-2 which performs a very critical function in viral replication. The initial lead peptide (Temporin L, TL) was identified based on computational screening. The FRET and selected ion monitoring (SIM) based assays showed an estimated IC50 of TL at 38.80 and 23.8 μM, respectively against the 3CLpro of SARS-CoV-2. Numerous staple and dimer peptides analogues were designed, synthesized, and tested their biological efficiency. The in-vitro investigation revealed that several analogues showed improved inhibition efficiency and the best α-methylated staple (TLP3M3) peptide demonstrated an estimated IC50 at 284 nanomolar (nM) and outstanding (~8h) serum stability. This study showed that the best peptide candidate will further be improved through structural-based rational design for Covid treatment.