Symposium of Student Scholars

Antiviral-Cell Penetrating Peptide Conjugate as Leads for Targeting the Main Protease of SARS-CoV-2

Peptides play an important role in the immune defenses of the host against several distinct types of infections. Hence, peptides represent a promising therapeutic approach for the treatment of SARS-CoV-2 infections. Temporin L, known for its antimicrobial characteristics, has an alpha-helical structure that has been found to interact with the cytoplasmic membrane and induce the formation of pores. In-vitro assessment of the Temporin L1 inhibitor was found to exhibit moderate activity against Mpro of SARS-CoV-2. Notably, the conformational analysis suggests that the rigid structure of Temporin L (TL) facilitates favorable binding to Mpro's active site. Here, we introduce a new approach to the design, synthesis, and characterization of the conjugation of Temporin L to various cell-penetrating peptides (CPP) inhibitors targeting the main protease (Mpro) of SARS-CoV-2. This conjugation can be able to enhance 4- to 16-fold antiviral activity. Our theoretical study of the SARS-CoV-2 Mpro suggests that the TL-CPP inhibitor can bind the active site of Mpro in the predicted manner. The structural insights observed from Molecular Dynamics (MD) simulations provide a clearer understanding of how the conjugate TL-CPP peptide inhibitor could interact with Mpro's active site. Liquid chromatography coupled with mass spectrometry (LC-MS) was used to characterize the peptide intermediates, demonstrating that experimental m/z values corresponded with theoretical m/z values. Subsequently, the results of our study provide crucial insight into the therapeutic approach of developing peptide inhibitors against the main protease of SARS-CoV-2. Furthermore, the findings of this study provide a groundwork understanding of the in-vitro main protease assay validation to identify the lead conjugate TL-CPP peptides targeting SARS-CoV-2.