Nanomolar inhibitors of Mycobacterium tuberculosis glutamine synthetase 1: Synthesis, biological evaluation and X-ray crystallographic studies

Glutamine Synthetase Drugability beyond Its Active Site: Exploring Oligomerization Interfaces and Pockets

“…All three enzymes depend on oligomerization to become active, given that the active site is located in between monomers. Inhibitors directed to this enzyme are currently on high demand, as can be seen by the number of recent papers dedicated to design new inhibitors of GS [14,17,18,20,21,22,23,24,26,54,55,56,57,58,59]. However, all of them are designed to act on the GS active site, lacking on specificity against one particular organism or group of organisms.…”

“…Evidences indicate that glufosinate may be a major danger with both environmental and human health repercussions [11,12,13,14,15,16]. In the pharmaceutical field, studies aimed to differentiate bacterial GS I from mammal GS II have been carried out with the expectation of developing new antibiotics, especially against tuberculosis where GS has proven, in vitro, to be an excellent target for anti-tuberculosis drug development [17,18,19,20,21]. Multiple efforts have been done in the last two decades to attain novel inhibitors of GS that can act as anti-tuberculosis therapeutic agents.…”

“…The second category is dedicated to inhibitors targeting the ATP binding site, which normally are bigger hydrophobic heterocycles that bind to a larger and less conserved region of the active site, aiming more selective inhibition than inhibitors such PPT or MSO. Inhibitors from both categories have been already co-crystalized with mtGS, providing insights about their action mechanism [21,22,23,24,25,26]. Either way, all of them bind in the active site or its vicinity.…”

Glutamine synthetase structure‐catalysis relationship—Recent advances and applications

“…Several studies prospected new antibiotics based on the distinct features of GSI and GSII, in particular for tuberculosis, for which GS is a proved excellent target. 46,[67][68][69][70] The loss of tuberculosis pathogenicity is due to the lack of formation of the cell wall component poly-L-glutamate-glutamine and the inability to modulate the acid level inside phagosomes. 69 The efficiency of mtGSI inhibition, as a tuberculosis therapeutical drug, was later proved in mammal guinea pigs.…”

“…46 However, until now there is no available drug in the market to treat tuberculosis that relies on GS inhibition. Recent studies aiming at mtGSI selective inhibition are exploring the ATP binding pocket, 48,67,70 the intermonomer interfaces, 40 or targeting the adenylated form of mtGSI. 71 GS inhibition in humans has been studied in animal models for neurodegenerative disorders.…”