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.

Investigation of Streptomyces sp. Strain EMB24 Secondary Metabolite Profile Has Unraveled Its Extraordinary Antibacterial Potency Against Drug-Resistant Bacteria.

With the overuse and misuse of antibiotics amid COVID-19 pandemic, the antimicrobial resistance, which is already a global challenge, has accelerated its pace significantly. Finding novel and potential antibiotics seems one of the probable solutions. In this work, a novel Streptomyces sp. strain EMB24 was isolated and found to be an excellent source of antimicrobials as confirmed by agar-plug assay. It showed antibacterial activity against infection-causing bacteria, namely Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. In addition, Streptomyces sp. strain EMB24 inhibited the growth methicillin-resistant Staphylococcus aureus (MRSA), tetracycline-resistant Neisseria gonorrhoeae, and ampicillin-resistant Neisseria gonorrhoeae. Furthermore, to get deep insights about the genome and biosynthetic gene clusters producing antibiotics, whole genome sequencing was done. The strain EMB24 is closely related to the Streptomyces longispororuber as revealed by phylogenetic analysis which is a potential source of antibiotics and pigments as undecylprodigiosin and metacycloprodigiosin belonging to the class prodigiosin. Naphthyridinomycin, alkylresorcinols, desferrioxamine B and E, venezuelin, aborycin, MS-271, and siamycin are potent therapeutics that shared 100% similarity with the reference strain as revealed by the online antiSMASH tool.

Genomic discovery of an evolutionarily programmed modality for small-molecule targeting of an intractable protein surface.

The vast majority of intracellular protein targets are refractory toward small-molecule therapeutic engagement, and additional therapeutic modalities are needed to overcome this deficiency. Here, the identification and characterization of a natural product, WDB002, reveals a therapeutic modality that dramatically expands the currently accepted limits of druggability. WDB002, in complex with the FK506-binding protein (FKBP12), potently and selectively binds the human centrosomal protein 250 (CEP250), resulting in disruption of CEP250 function in cells. The recognition mode is unprecedented in that the targeted domain of CEP250 is a coiled coil and is topologically featureless, embodying both a structural motif and surface topology previously considered on the extreme limits of "undruggability" for an intracellular target. Structural studies reveal extensive protein-WDB002 and protein-protein contacts, with the latter being distinct from those seen in FKBP12 ternary complexes formed by FK506 and rapamycin. Outward-facing structural changes in a bound small molecule can thus reprogram FKBP12 to engage diverse, otherwise "undruggable" targets. The flat-targeting modality demonstrated here has the potential to expand the druggable target range of small-molecule therapeutics. As CEP250 was recently found to be an interaction partner with the Nsp13 protein of the SARS-CoV-2 virus that causes COVID-19 disease, it is possible that WDB002 or an analog may exert useful antiviral activity through its ability to form high-affinity ternary complexes containing CEP250 and FKBP12.