Remdesivir – a Battle against COVID-19
Remdesivir is a broad-spectrum antiviral agent. Developed by Gilead Sciences, Inc., one of the leading biotech companies of the United States, it is sold under the brand name of Veklury. In October, 2020, remdesivir was approved by the Food and Drug Administration (FDA) for the treatment of COVID-19.
Target identified
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virus contains a single stranded positive-sense RNA genome ~ 29.9 kilo base pairs in size. After entering the susceptible cell, the genome functions as a messenger RNA (mRNA) which is translated leading to the synthesis of sixteen non-structural proteins (NSP 1-16). Of these, the catalytic NSP12, together with the accessory proteins NSP7 and NSP8, constitutes an RNA dependent RNA polymerase (RdRp) – the replication/transcription machinery of the virus. Besides an N-terminal extension, NSP12 consists of three domains – fingers, palm and thumb. A “grip” (hole) formed between these three domains serve as the binding site for the RNA template and nucleoside triphosphates (NTPs).
Remdesivir – an adenosine analog that dupes viral replication/transcription machinery
For RNA-dependent RNA elongation, the 3¢-terminal nucleotide of the synthesizing RNA chain is positioned at the -1 site of the template RNA and the incoming nucleoside triphosphate (NTP) binds to the adjacent +1 site after being subjected to selection at multiple stages. The corresponding nucleoside monophosphate (NMP) is then added to the 3¢-end of the growing RNA chain by the RdRp via phosphoryl-transfer reaction. The incorporation triggers RNA translocation and vacates the + 1 site for the next incoming NTP to bind.
Remdesivir is a prodrug that mimics the structure of adenosine. As it enters the cell, it is metabolized (phosphorylated) to an active nucleotide triphosphate (NTP) analog called remdesivir triphosphate (RTP). The RdRp can use RTP as a substrate to incorporate remdesivir monophosphate (RMP) into the growing RNA strand. This is hardly surprising as comparative modelling has shown that RTP can bind to the active site of CoV-2 NSP12 in a manner similar to the binding of native adenosine triphosphate (ATP) to a structurally similar RdRp. RMP mimics adenosine monophosphate (AMP) and forms Watson-Crick base pair with uridine monophosphate (UMP).
Nonetheless, incorporation of remdesivir into the growing RNA product allows the addition of three more nucleotides downstream before terminating RNA synthesis – remdesivir is a “chain terminator”. This property of remdesivir arises from the substitution of a cyano group at the C1¢ of its ribose moiety. After the three nucleotides have been added, and the RMP is at -4 position (with respect to the 3¢-end) of the RNA chain, the C1¢-cyano (a) can destabilize the salt bridge between an aspartate residue (D865) and a lysine residue (K593) of NSP12, and/or (b) be involved in a steric clash with the side chain of a serine residue (S861) in NSP12. As a consequence, RNA translocation is impaired.
Remdesivir is not without its side-effects – careful optimization of its application is a compelling requirement. Studies on the efficacy and drawbacks of remdesivir treatment are ongoing and newer results are likely to emerge.