Executive Summary : | The FDA approved Remdesivir for treating COVID-19 patients in October 2020, highlighting the importance of nucleotides and nucleosides in the scientific community. The drug, developed at Gilead, was initially used for treating Ebola virus and has undergone significant development in its structure and activity relationships. Nucleosides, which are similar to naturally occurring ATP, provide better molecular recognition by various enzymes in cells. C-nucleotides are stable towards enzymatic hydrolysis compared to N-nucleotides. Structural modifications on nucleotides can have both positive and negative effects on their biological activity. Researchers in Gilead studied the disubstitution of ribose C-1 position with various small substituents, observing enhanced inhibitory activity against various virus families. The role of 1'-CN substituent has been explored through MD simulations, with 1'-cyano experiencing electrostatic interaction with the Asp865-Lys593 salt bridge, stopping the translocation in the RNA-dependent RNA polymerase enzyme (RdRp). Computational groups and Cryo-EM models have provided evidence of the stalling of translocation of RNA strand caused by Remdesivir and further stopping viral replication. Despite its widespread use in COVID-19 hospitalization, Remdesivir has been associated with hepatotoxicity, respiratory and reproductive toxicity, and nephrotoxicity. Pharmacokinetics of Remdesivir have shown the distribution of various metabolites within the lungs, kidneys, and testes. The ongoing pandemic has prompted a collaborative and rapid research output to combat the consequences of COVID infection. |