Evaluation of Biomimetic Antimicrobial Peptides Targeting the Main Protease of Sars-CoV-2

The Covid-19 pandemic has emphasized the urgent need for the development of effective and economical antiviral treatments. Sars-CoV-2, the causative agent of Covid-19, is a single stranded positive sense RNA virus that encodes for 29 proteins; one of which is the main protease (Mpro), a cysteine protease which plays a pivotal role in the proper cleavage of nascent viral polyproteins during replication. Mpro is a key target for inhibition in the development of therapeutic agents treating Covid-19; nevertheless, research and development of novel antivirals for known targets is still a time consuming and financially costly endeavor. However, molecular dynamics modeling has afforded a unique opportunity to quickly screen a great multitude of possible inhibitors without upfronting the cost of producing said inhibitors. Previously, our group utilized this technique to computationally screen a group of naturally occurring antimicrobial products against Mpro. These simulations yielded several viable peptide sequences which were expected to bind tightly to the Mpro active site. Therapeutic peptides are synthetically accessible via Fmoc-solid phase synthesis and are known to have high specificity, thus possess the potential of being potent low-cost drugs. A strong peptide candidate (DRAMP18160) was chosen from the group of computationally screened peptides and subjected to a series of in-vitro analyses to determine its effectiveness at inhibiting the function of Mpro. By utilizing Fӧrster resonance energy transfer based end point assays, it was found that DRAMP18160 displayed an IC50 value of 59 μM which further establishes the viability of natural product repurposing for widespread antiviral applications