A Survey of Inhibitors for the Main Protease of Coronaviruses with the Potential for Development of Broad-Spectrum Therapeutics

The coronaviruses plaguing humanity in the 21st century share much in common: a spontaneous route of origin from wild animals, a propensity to take human life, and, importantly, a highly conserved set of biological machinery necessary for viral replication. Most recently, the SARS-CoV-2 is decimating economies around the world and has claimed over two million human lives, reminding the world of a need for an effective drug against present and future coronaviruses. To date, attempts to repurpose clinically approved antiviral medications show minimal promise, highlighting the need for development of new antiviral drugs. Nucleotide analog inhibitors are a promising therapeutic candidate, but early data from clinical studies suggests these compounds have limited efficacy. However, novel compounds targeting the main protease responsible for critical steps in viral assembly are gaining considerable interest because they offer the potential for broad-spectrum coronavirus therapy. Here, we review the literature regarding potential inhibitors for the main protease of coronaviruses, especially SARS-CoV-2, analyze receptor-drug interactions, and draw conclusions about candidate inhibitors for future outbreaks. Promising candidates for development of a broad-spectrum coronavirus protease inhibitor include the neuraminidase inhibitor 3K, the peptidomimetic inhibitor 11a and 11b, the α-ketoamide inhibitor 13b, the aldehyde prodrug, and the phosphate prodrug developed by Pfizer. In silico and in vitro analyses have shown that these inhibitors strongly interact with the active site of the main protease, and to varying degrees, prevent viral replication via interactions with the largely conserved active site pockets. KEYWORDS: Severe Acute Respiratory Syndrome Coronavirus; Middle East Respiratory Syndrome Coronavirus; Severe Acute Respiratory Syndrome Coronavirus 2; Replicase Polypeptide; Protease; Neuraminidase Inhibitor; Peptidomimetic Inhibitor; α-Ketoamide Inhibitor; Molecular Docking