Breaking Barriers: Current Advances and Future Directions in Mpox Therapy.

BACKGROUND: Mpox, a newly discovered zoonotic infection, can be transmitted from animal to human and between humans. Serological and genomic studies are used to identify the virus. OBJECTIVE: Currently, there are no proven effective treatments for Mpox. Also, the safety and efficacy of intravenous vaccinia immune globulin, oral Tecovirimat (an inhibitor of intracellular viral release), and oral Brincidofovir (a DNA polymerase inhibitor) against the Mpox virus are uncertain, highlighting the need for more effective and safe treatments. As a result, drug repurposing has emerged as a promising strategy to identify previously licensed drugs that can be repurposed to treat Mpox. RESULTS: Various approaches have been employed to identify previously approved drugs that can target specific Mpox virus proteins, including thymidylate kinase, D9 decapping enzyme, E8 protein, Topoisomerase1, p37, envelope proteins (D13, A26, and H3), F13 protein, virus's main cysteine proteases, and DNA polymerase. CONCLUSION: In this summary, we provide an overview of potential drugs that could be used to treat Mpox and discuss the underlying biological processes of their actions.

Interleukin-1ß converting enzyme (ICE): A comprehensive review on discovery and development of caspase-1 inhibitors.

Caspase-1 is a critical mediator of the inflammatory process by activating various pro-inflammatory cytokines such as pro-IL-1ß, IL-18 and IL-33. Uncontrolled activation of caspase-1 leads to various cytokines-mediated diseases. Thus, inhibition of Caspase-1 is considered therapeutically beneficial to halt the progression of such diseases. Currently, rilonacept, canakinumab and anakinra are in use for caspase-1-mediated autoinflammatory diseases. However, the poor pharmacokinetic profile of these peptides limits their use as therapeutic agents. Therefore, several peptidomimetic inhibitors have been developed, but only a few compounds (VX-740, VX-765) have advanced to clinical trials; because of their toxic profile. Several small molecule inhibitors have also been progressing based on the three-dimensional structure of caspase-1. However there is no successful candidate available clinically. In this perspective, we highlight the mechanism of caspase-1 activation, its therapeutic potential as a disease target and potential therapeutic strategies targeting caspase-1 with their limitations.

Insights into the structural requirements of triazole derivatives as promising DPP IV inhibitors: computational investigations.

Diabetes is one of the leading causes of death globally as per World Health Organization 2019. To cope up with side effects of current diabetes therapy, researchers have found several novel targets for the treatment of diabetes. Currently, dipeptidyl peptidase IV (DPP IV) has emerged as a target in modulating the diabetes physiology. In the present work, various 3D-Quantitative structure activity relationship (QSAR) techniques namely comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis, topomer CoMFA and molecular hologram QSAR are used to explore the structural requirements of triazole derivatives as DPP IV inhibitors. Different models generated by 3D QSAR studies had acceptable statistical values for further prediction of molecules. From the contour maps of QSAR results, important structural features are deduced. Substitutions on N1 and N2 of triazole ring with H-bond donor group enhances the biological activity. Aliphatic side chain, less bulky group, H-bond donor group and -COOH group on N3 of triazole ring are vital for the DPP IV inhibition. Moreover, electron withdrawing side chain on the triazole ring improves the biological activity. Further, novel triazole derivatives were designed and docking results of these compounds proved the efficiency of the developed 3D QSAR model. In future, results of this study may provide promising DPP IV inhibitors for the treatment of diabetes. Communicated by Ramaswamy H. Sarma.

Pharmacophore- based virtual screening, 3D- QSAR, molecular docking approach for identification of potential dipeptidyl peptidase IV inhibitors.

Pharmacophore modeling, molecular docking, and in silico ADME studies have been carried out to determine the binding mode and drug likeliness profile of Pyrrolidine derivatives as Dipeptidyl peptidase IV inhibitors. A five point pharmacophore model (AAADH_1) was generated using 96 compounds with IC50 values ranging from 1.8 to 13000 nM. A statistically significant 3D-QSAR model was generated from the pharmacophore hypothesis. The model had a high correlation coefficient (R2 - 0.92), cross validation coefficient (Q2 - 0.776) and F value (F - 144) at 6 component Partial least square factor. Pearson r of 0.7124 indicated greater degree of confidence on the model. The accuracy and predictability of the generated model were checked by Enrichment factor, Receiver operating characteristic curves, area under curve, Boltzmann-enhanced discrimination of Receiver operating characteristic and the Robust initial enhancement. To identify novel and potent Dipeptidyl peptidase IV inhibitors, virtual screening was performed using the ligand and database screening. Considering the potent hit molecules on the basis of pharmacophore virtual screening, we have designed new molecules and further subjected to see the interaction with protein. The catalytic domain of Dipeptidyl peptidase IV enzyme in complex with Vildagliptin (PDB Code: 6B1E) was obtained from protein data bank with resolution 1.77 A°. Compound 75 showed the better binding (dock score -7.966) with protein than standard drug vildagliptin (Dock Score -6.554). The hits obtained on virtual screening of the database have provided new chemical starting points for design and development of novel Dipeptidyl peptidase IV inhibitory agents.Communicated by Ramaswamy H. Sarma.

Recent Medicinal Chemistry Approach for the Development of Dipeptidyl Peptidase IV Inhibitors.

BACKGROUND: Diabetes, a metabolic disease, occurs due to a decreased or no effect of insulin on the blood glucose level. The current oral medications stimulate insulin release, increase glucose absorption and its utilization, and decrease hepatic glucose output. Two major incretin hormones like Glucose-dependent insulinotropic polypeptide (GIP) and glucagonlike peptide - 1 (GLP-1) stimulate insulin release after a meal, but their action is inhibited by enzyme dipeptidyl peptidase- IV. OBJECTIVE: The activity of endogenous GLP-1 and GIP prolongs and extends with DPP IV inhibitors, which are responsible for the stimulation of insulin secretion and regulation of blood glucose level. DPP IV inhibitors have shown effectiveness and endurability with a neutral effect on weight as well as less chances of hypoglycemia in the management of type 2 diabetes. These journeys started from Sitagliptin (marketed in 2006) to Evogliptin (marketed in 2015, Korea). CONCLUSION: Treatment of type 2 diabetes includes lifestyle changes, oral medications, and insulin. Newer and superior therapies are needed more than currently prescribed drugs. Various heterocyclic derivatives have been tried, but due to masking of DASH proteins, CYP enzymes, and hERG channel, they showed side effects. Based on these, the study has been focused on the development of safe, influential, selective, and long-lasting inhibitors of DPP IV.