Identification of core therapeutic targets for Monkeypox virus and repurposing potential of drugs against them: An in silico approach.

Monkeypox virus (mpox virus) outbreak has rapidly spread to 82 non-endemic countries. Although it primarily causes skin lesions, secondary complications and high mortality (1-10%) in vulnerable populations have made it an emerging threat. Since there is no specific vaccine/antiviral, it is desirable to repurpose existing drugs against mpox virus. With little knowledge about the lifecycle of mpox virus, identifying potential inhibitors is a challenge. Nevertheless, the available genomes of mpox virus in public databases represent a goldmine of untapped possibilities to identify druggable targets for the structure-based identification of inhibitors. Leveraging this resource, we combined genomics and subtractive proteomics to identify highly druggable core proteins of mpox virus. This was followed by virtual screening to identify inhibitors with affinities for multiple targets. 125 publicly available genomes of mpox virus were mined to identify 69 highly conserved proteins. These proteins were then curated manually. These curated proteins were funnelled through a subtractive proteomics pipeline to identify 4 highly druggable, non-host homologous targets namely; A20R, I7L, Top1B and VETFS. High-throughput virtual screening of 5893 highly curated approved/investigational drugs led to the identification of common as well as unique potential inhibitors with high binding affinities. The common inhibitors, i.e., batefenterol, burixafor and eluxadoline were further validated by molecular dynamics simulation to identify their best potential binding modes. The affinity of these inhibitors suggests their repurposing potential. This work can encourage further experimental validation for possible therapeutic management of mpox.

Quercetin against Emerging RNA Viral Diseases: Potential and Challenges for Translation.

Because of higher adaptability and mutability, there is always a possibility for RNA viral disease outbreaks. There are no approved antivirals for the majority of RNA viruses including SARS-CoV-2, CHIKV, DENV, JEV, ZIKV, and EBOV. To treat these infections and to prepare for future epidemics there is a necessity to identify effective therapeutic strategies with broad-spectrum actions against RNA viruses. Unregulated inflammation is the major cause of the severity associated with these viral diseases. Quercetin is a privileged molecule that is known to interfere at different levels of inflammatory response. Besides, it modulates pathways responsible for viral translation as well as the immune response of the host. It has also been found to inhibit replication by targeting critical targets of some of these viruses. Because of the abilities to inhibit viral targets, modulate host factors, or a combination of both; quercetin has been demonstrated to help recover from some of these viral diseases in preclinical /clinical studies. Thus, it can be a drug candidate for application against a broad range of viral diseases. However, its translational value is limited by the lack of large-scale clinical studies. A major hurdle for oral application is poor solubility. Thus, developing a suitable form of quercetin can enable adequate bioavailability leading to its translational application.