Targeting SARS-CoV-2 Polymerase with New Nucleoside Analogues

Abstract

Despite the fact that COVID-19 vaccines are already available on the market, there have not been any effective FDA-approved drugs to treat this disease. There are several already known drugs that through drug repositioning have shown an inhibitory activity against SARS-CoV-2 RNA-dependent RNA polymerase. These drugs are included in the family of nucleoside analogues. In our efforts, we synthesized a group of new nucleoside analogues, which are modified at the sugar moiety that is replaced by a quinazoline entity. Different nucleobase derivatives are used in order to increase the inhibition. Five new nucleoside analogues were evaluated with in vitro assays for targeting polymerase of SARS-CoV-2.

2′- and 3′-Ribose Modifications of Nucleotide Analogues Establish the Structural Basis to Inhibit the Viral Replication of SARS-CoV-2

“…Inhibitors can be developed to target the functional states or the dynamic transitions in the cycle to impair the processivity of nucleotide addition. As nucleoside triphosphate is the substrate for RdRp to start the extension of the nascent strand in each cycle (Figure A), nucleotide analogues that have similar chemical structures to the cognate substrate but with chemical modifications on either the base or the ribose hold great potential as antiviral drugs that target SARS-CoV-2 RdRp. ,,− …”

A Landscape of CRISPR/Cas Technique for Emerging Viral Disease Diagnostics and Therapeutics: Progress and Prospects

“…CRISPR/Cas-based methods have high specificity and sensitivity without the need for expensive equipment, in contrast to conventional laboratory methods for detecting COVID-19, such as RT-qPCR and next-generation sequencing (NGS), which demand highly skilled technicians and expensive facilities, and serological tests that recognise antibodies specific to SARS-CoV-2 in later stages of infection. CRISPR/Cas-based methods would be ideal for simple tests that are crucial for the diagnosis of COVID-19 because of their high precision, specificity, portability, and minimal equipment requirements, particularly in developing nations or locations with a higher risk of infection, such as airports, ports, and emergency rooms [ 161 , 162 , 163 , 164 , 165 ].…”

“…As in the case of COVID infection, viral burden generally changes throughout the day and at dissimilar steps of septicity. Consequently, a qRT–PCR assessment might show false negative at the time when the viral burden is little, but it does not eliminate contagion, and hence, a more precise investigation is obligatory [ 161 ]. One of the most important strengths of the CRISPR/Cas diagnosis is its gRNA selection, which is taken from the conserved genomic locus among the variants of viruses.…”

Identification of potential targets against SARS‐CoV‐2 of antiviral drugs based on photoaffinity probes

“…These unnatural nucleotides are then incorporated into the replicating viral genome, resulting in chain termination and blocking of replication or transcription (Pruijssers & Denison, 2019). The incorporation of nucleoside analogs into extended nucleoside chains results in mutations that, in turn, alter viral biological processes (Daikopoulou et al, 2021; Wang et al, 2021; Zenchenko et al, 2021). Nucleoside analogues can be used to inhibit the broad‐spectrum virus column and overcome drug resistance as most of the polymerases shared by nucleosides are used as inhibition sites in antiviral therapy, and nucleotide binding sites in viruses of different families are all conserved sites.…”