Molecular mechanisms of RNA-dependent RNA polymerase inhibition from traditional bioactive medicine

Abstract

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spread quickly. The continuous transmission of a novel coronavirus and its capacity to spread between individuals motivated scientists to develop novel treatment strategies for future COVID-19-like pandemics. RNA-dependent RNA polymerase (RdRp) is a crucial enzyme involved in the replication of viral RNA. It is considered the most favorable target for antiviral medication development due to its absence in human cells and its high level of conservation among coronaviruses. A recent study demonstrated that remdesivir and chloroquine efficiently impede the replication and infection of SARS-CoV-2 and 2019 novel Coronavirus (2019-nCov) in laboratory conditions. These structures also provide insight into the mechanism of RdRp inhibition by nucleotide inhibitors and serve as a molecular blueprint for the creation of medications that target RdRp. In January 2020, a single case of COVID-19 in the United States was effectively treated using remdesivir under compassionate use. Furthermore, scientific evidence has shown that camostat mesylate, a protease inhibitor that has been tested in clinical trials, effectively blocks the infection of Calu-3 cells by SARS-CoV-2 and prevents the entry of the SARS-2 spike protein (S protein) into primary human lung cells. In this chapter, we specifically address the pharmacological treatments that target RdRp, proteinase, and S protein to treat SARS-CoV-2-like infections. This chapter aims to elucidate the underlying justification for targeting RdRp enzymes as novel therapeutic strategies for the treatment of COVID-19-like viral-infected patients. Furthermore, we will explore the feasibility and difficulties in targeting RdRp and proteinase, as well as the utilization of the natural product quinoline and its analog chloroquine for the treatment of coronavirus infection. Ultimately, understanding the structural-functional connections of the S protein of SARS-CoV-2 will offer fresh perspectives on how to prevent interactions between the S protein and angiotensin-converting enzyme 2 (ACE2). This knowledge will also aid in the development of innovative therapeutic strategies for the novel coronavirus SARS-CoV-2-like pandemic in the future. © 2025 Taylor & Francis Group, LLC.