Inhibition Efficiency of Linear and Cyclic Temporin L Analogues against the Main Protease of SARS-CoV-2
Disciplines
Analytical Chemistry | Biochemistry | Medicinal-Pharmaceutical Chemistry
Abstract (300 words maximum)
Main protease (Mpro) of SARS-CoV-2 plays key roles in replicating the virus when it enters into the host-system. Mpro is not found in the host-system and hence it will be very selective and safe to inhibit this protease. An effective inhibitor would block the two amino acids (Cys145 and His41) present in the catalytic dyad of the Mpro. Although two oral antiviral drugs are available in the market, small molecule drugs induce side effect and resistance. Peptides can play a vital role in inhibiting the catalytic sites of Mpro as they are more effective, selective and induce less side effects and resistance. However, peptides are not stable in the stomach as they degrade quickly due to the presence of various proteolytic enzymes. Previous studies from our group showed that Temporin L can effectively inhibit the main protease, however, this peptide showed a short half-life. The overall goal of this project is to develop cyclic analogues of Temporin L investigating their inhibition efficiency and improving the serum half-life. Initially, a linear Temporin L analogue containing two cysteine amino acids was synthesized by solid phase peptide synthesis. The cyclic analogue was prepared by dissolving it with 10% DMSO and stirring it for 48 hours. Both peptides’ masses were confirmed by LTQ mass spectrometer. Selected ion monitoring (SIM) based liquid chromatography-mass spectroscopy (LC-MS) assay was used to evaluate and compare the in-vitro biological activity of linear and cyclic analogues. The inhibition efficiency of the linear peptide demonstrated a IC50 value of 16.6 µM in SIM assay. Remarkably, the cyclic analogues showed a slightly strong inhibition efficiency with a IC50 value of 13.2 µM in SIM assays, respectively. Future studies will be directed to synthesize more cyclic analogues and test their serum stability.
Academic department under which the project should be listed
CSM - Chemistry and Biochemistry
Primary Investigator (PI) Name
Mohammad A. Halim
Inhibition Efficiency of Linear and Cyclic Temporin L Analogues against the Main Protease of SARS-CoV-2
Main protease (Mpro) of SARS-CoV-2 plays key roles in replicating the virus when it enters into the host-system. Mpro is not found in the host-system and hence it will be very selective and safe to inhibit this protease. An effective inhibitor would block the two amino acids (Cys145 and His41) present in the catalytic dyad of the Mpro. Although two oral antiviral drugs are available in the market, small molecule drugs induce side effect and resistance. Peptides can play a vital role in inhibiting the catalytic sites of Mpro as they are more effective, selective and induce less side effects and resistance. However, peptides are not stable in the stomach as they degrade quickly due to the presence of various proteolytic enzymes. Previous studies from our group showed that Temporin L can effectively inhibit the main protease, however, this peptide showed a short half-life. The overall goal of this project is to develop cyclic analogues of Temporin L investigating their inhibition efficiency and improving the serum half-life. Initially, a linear Temporin L analogue containing two cysteine amino acids was synthesized by solid phase peptide synthesis. The cyclic analogue was prepared by dissolving it with 10% DMSO and stirring it for 48 hours. Both peptides’ masses were confirmed by LTQ mass spectrometer. Selected ion monitoring (SIM) based liquid chromatography-mass spectroscopy (LC-MS) assay was used to evaluate and compare the in-vitro biological activity of linear and cyclic analogues. The inhibition efficiency of the linear peptide demonstrated a IC50 value of 16.6 µM in SIM assay. Remarkably, the cyclic analogues showed a slightly strong inhibition efficiency with a IC50 value of 13.2 µM in SIM assays, respectively. Future studies will be directed to synthesize more cyclic analogues and test their serum stability.