Target-based drug design strategies to overcome resistance to antiviral agents: opportunities and challenges

Small Molecule Drugs Targeting Viral Polymerases

“…Consequently, this presents a significant threat that requires extensive research efforts to investigate diverse strategies aimed at designing and developing next-generation small molecule inhibitors with heightened potency against drug-resistant viral strains. This involves, but is not limited to, the use of high-throughput screening technologies and advanced computational modelling/artificial intelligence methods to identify novel chemical scaffolds and refining existing inhibitors for improved resistance profiles [118,[179][180][181][182]. Strategies may include, for example, targeting conserved regions of the enzyme that are less prone to mutation or designing molecules with increased structural flexibility (as demonstrated by second-generation HIV NNRTIs compared to their first-generation counterparts), the latter being able to dynamically adjust their binding modes in response to mutations, thereby preserving their efficacy against viral strains that have acquired resistance.…”

“…Ebola virus; 2 severe acute respiratory syndrome coronavirus 2; 3 Middle East respiratory syndrome coronavirus; 4 severe acute respiratory syndrome;5 Zika virus;6 Crimean-Congo hemorrhagic fever virus;7 Marburg virus;8 Henipa Virus;9 Nipah virus; 10 Lassa fever virus;11 Rift Valley virus.Finally, there is a pressing need for the optimization of combination antiviral therapy[180,181,186,187]. This imperative arises from the complexity and adaptability of viruses, which can develop resistance to single-drug treatments over time.…”

Advancements in Antiviral Drug Development: Comprehensive Insights into Design Strategies and Mechanisms Targeting Key Viral Proteins

“…The nucleic acid sequence changes lead to the structural transformation of the translated proteins that serve as drug targets, such as the viral polymerase, protease, and surface proteins, which in turn cause the drug to be ineffective or show reduced efficacy. To prevent the emergence of drug-resistant mutations, the optimal combination of drug regimen and dosage should be adopted to maximally inhibit viral replication to reduce or delay the emergence of drug resistance [ 93 ]. Drug combinations can yield superior clinical outcomes with lower drug resistance, as the treatment of AIDS has adopted highly active anti-retroviral therapy (HAART).…”

“…Drug combinations can yield superior clinical outcomes with lower drug resistance, as the treatment of AIDS has adopted highly active anti-retroviral therapy (HAART). Target-based approaches for the design of antiviral drugs can play a pivotal role in combating drug-resistant challenges by enhancing compound-target affinity while minimizing interactions with mutated binding pockets [ 93 ]. Viral load monitoring and viral genotyping are carried out to select more appropriate drugs [ 94 - 96 ].…”

“…Inhibiting viral replication and facilitating prompt viral clearance from a host perspective remain crucial facets of antiviral therapeutic strategies. Additionally, host-targeting antiviral drugs offer a promising avenue for circumventing viral mutation [ 93 ]. In our research we found that RNA modification m 6 A-mediated downregulation of the OGDH-Itaconate pathway reprograms cellular metabolism to inhibit viral replication, proposing potential targets for controlling viral infection [ 99 ].…”