Recent Advances in Molecular Mechanisms of Nucleoside Antivirals

Abstract

The search for new drugs has been greatly accelerated by the emergence of new viruses and drug-resistant strains of known pathogens. Nucleoside analogues (NAs) are a prospective class of antivirals due to known safety profiles, which are important for rapid repurposing in the fight against emerging pathogens. Recent improvements in research methods have revealed new unexpected details in the mechanisms of action of NAs that can pave the way for new approaches for the further development of effective drugs. This review accounts advanced techniques in viral polymerase targeting, new viral and host enzyme targeting approaches, and prodrug-based strategies for the development of antiviral NAs.

Adenine, a key player in biology and medicinal chemistry

“…During DNA/RNA chain elongation, the (n + 1) nucleoside triphosphate is attached to the 3 ′ -OH of the n terminal nucleotide of the growing chain. The 3 ′ -OH group is thus essential for chain elongation and "obligate chain terminators" nucleoside analogues lack the 3 ′ -OH group so that their incorporation consequently results in chain termination [134]. Either the 3 ′ -OH group is substituted with a non-reactive group (-H, -Cl, -F, -Br and -N 3 for example) or the deoxyribose is replaced by arabinose derivatives.…”

“…These compounds exhibit a locked sugar conformation, and after their incorporation in the growing chain, two or three other nucleotides can be further incorporated. Then, due to steric hindrance and displacement of the growing chain in the catalytic site, strand elongation is impeded [134]. This mechanism was developed to avoid exonucleolytic re- moval of nucleoside analogues.…”

Marine-Derived Bioactive Metabolites as a Potential Therapeutic Intervention in Managing Viral Diseases: Insights from the SARS-CoV-2 In Silico and Pre-Clinical Studies

“…Vaccines are regarded as the most effective method for preventing viral infections [ 13 ]. Despite intensive research on a variety of viral pathogens, including the recent coronavirus strains, the repertoire of available antiviral treatments remains limited, compounded by the concerning decline in efficacy over time against certain viruses [ 14 , 15 , 16 ].…”

Nucleoside‐Based Drug Target with General Antimicrobial Screening and Specific Computational Studies against SARS‐CoV‐2 Main Protease

“…[95] The development of antiviral drugs is a complex and iterative process. [96] It involves synthesizing and testing numerous compounds, optimizing their chemical structures for better binding and reduced side effects, and conducting rigorous preclinical and clinical trials to ensure safety and efficacy. [97] Novel nucleoside triphosphate (NTP) analogs with C2' or C3' carbon quaternary centers, two of which demonstrate inhibitory effectiveness against the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2.…”

“…The development of antiviral drugs is a complex and iterative process [96] . It involves synthesizing and testing numerous compounds, optimizing their chemical structures for better binding and reduced side effects, and conducting rigorous preclinical and clinical trials to ensure safety and efficacy [97] …”