Disruption of water networks is the cause of human/mouse species selectivity in urokinase plasminogen activator (uPA) inhibitors derived from hexamethylene amiloride (HMA)

The urokinase plasminogen activator (uPA) plays a critical role in tumor cell invasion and migration and is a promising anti-metastasis target. 6-Substituted analogs of 5-N,N-(hexamethylene)amiloride (HMA) are potent and selective uPA inhibitors that lack the diuretic and anti-kaliuretic properties of the parent drug amiloride. However, the compounds display pronounced selectivity for human over mouse uPA, thus confounding interpretation of data from human xenografted mouse models of cancer. Here, computational and experimental findings reveal that residue 99 is a key contributor to the observed species selectivity, whereby enthalpically unfavorable expulsion of a water molecule by the 5-N,N-hexamethylene ring occurs when residue 99 is Tyr (as in mouse uPA). Analog 7 lacking the 5-N,N-hexamethylene ring maintained similar water networks when bound to human and mouse uPA and displayed reduced selectivity, thus supporting this conclusion. The study will guide further optimization of dual-potent human/mouse uPA inhibitors from the amiloride class as anti-metastasis drugs.

Urokinase plasminogen activator as an anti-metastases target: Inhibitor design principles, recent amiloride derivatives and issues with human/mouse species selectivity

The urokinase plasminogen activator (uPA) is a widely studied anticancer drug target with multiple classes of inhibitors reported to date. Many of these inhibitors contain amidine or guanidine groups, while others lacking these show improved oral bioavailability. Most of the X-ray co-crystal structures of small molecule uPA inhibitors show a key salt bridge between the side-chain carboxylate of Asp189 in the S1 pocket of uPA. This review summarises the different classes of uPA inhibitors, their binding interactions and experimentally measured inhibitory potencies and highlights species selectivity issues with recent 6-substituted amiloride and 5‐N,N-(hexamethylene)amiloride (HMA) derivatives.

Urban market amplifies strong species selectivity in Amazonian artisanal fisheries

Despite Amazonia possessing the highest freshwater biodiversity on Earth, urban landing data show how huge fishing pressure is placed on only a dozen species. However, truly characterising the fishery and understanding the drivers of species selectivity is challenging, given the neglect of artisanal fishing activity, who may catch most of the Amazon’s fish. We register the catch of 824 fishing trips by interviewing artisanal fishers in their rural riverside communities. We use these data to characterise the artisanal fishery of the Rio Purus, the main fish source sub-system for the Amazon’s largest city (Manaus), and investigate the factors determining catch composition. Fishers caught 80 fish species, yet just four species made up over half of the harvested biomass. Urban markets appear to drive greater selectivity, with a significantly lower species diversity in commercial compared to subsistence catches. Fish catch composition varied significantly both seasonally and with geographical remoteness from Manaus. The spatial turnover in catch composition appears to be driven by urban access, with more commercially important species dominating where Manaus-based fish-buyers frequent. Our data may partially explain observed overfishing in some commercially important species, particularly as most Amazonians now live in urban areas.