Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase.

Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism.

Laparoscopic deroofing of a recurrent giant simple hepatic cyst in a geriatric female: Case report.

ABSTRACT: Liver cysts often have no symptoms, are benign and are usually encountered during routine abdominal imaging for other conditions. Giant cysts have a higher risk of complications. Recurrence is common, and most research papers support laparoscopic deroofing as the initial management modality even in the recurrent cases as it avoids the morbidity of laparotomy and gives better short- and long-term post-operative outcomes. Here, we present a case of a 68-year-old female who presented to the outpatient department with complaints of right-sided dull-aching abdominal pain, heaviness, early satiety and significant weight loss for the past 2 months. A laparoscopic drainage and deroofing were done, and histopathological examination of the cystic wall was consistent with benign pathology. The patient has been doing well for the past year.