DprE1 Inhibitors: Enduring Aspirations for Future Antituberculosis Drug Discovery.

DprE1 is a crucial enzyme involved in the cell wall synthesis of Mycobacterium tuberculosis and a promising target for antituberculosis drug development. However, its unique structural characteristics for ligand binding and association with DprE2 make developing new clinical compounds challenging. This review provides an in-depth analysis of the structural requirements for both covalent and non-covalent inhibitors, their 2D and 3D binding patterns, as well as their biological activity data in vitro and in vivo, including pharmacokinetic information. We also introduce a protein quality score (PQS) and an active-site map of the DprE1 enzyme to help medicinal chemists better understand DprE1 inhibition and develop new and effective anti-TB drugs. Furthermore, we examine the resistance mechanisms associated with DprE1 inhibitors to understand future developments due to resistance emergence. This comprehensive review offers insight into the DprE1 active site, including protein-binding maps, PQS, and graphical representations of known inhibitors, making it a valuable resource for medicinal chemists working on future antitubercular compounds.

Ethyl Pyruvate as a Potential Defense Intervention against Cytokine Storm in COVID-19?

COVID-19 is a deadly pandemic and has resulted in a huge loss of money and life in the past few months. It is well known that the SARS-CoV-2 gene mutates relatively slowly as compared to other viruses but still may create hurdles in developing vaccines. Therefore, there is a need to develop alternative routes for its management and treatment of COVID-19. Based on the severity of viral infection in COVID-19 patients, critically ill patients (∼5%, with old age, and comorbidities) are at high risk of morbidities. The reason for this severity in such patients is attributed to "misleading cytokine storm", which produces ARDS and results in the deaths of critically ill patients. In this connection, ethyl pyruvate (EP) controls these cytokines/chemokines, is an anti-inflammatory agent, and possesses a protective effect on the lungs, brain, heart, and mitochondria against various injuries. Considering these facts, we propose that the site-selective EP formulations (especially aerosols) could be the ultimate adjuvant therapy for the regulation of misleading cytokine storm in severely affected COVID-19 patients and could reduce the mortalities.