Modimelanotide

Despite significant need and historical trials, there are no effective drugs in use for the prevention or treatment of acute kidney injury (AKI). There are several promising agents in early clinical development for AKI and two trials have recently been terminated. There are also exciting new findings in pre-clinical AKI research. There is a need to take stock of current progress in the field to guide future drug development for AKI. Areas covered: The main clinical trial registries, PubMed and pharmaceutical company website searches were used to extract the most recent clinical trials for sterile, transplant and sepsis-associated AKI. We summarise the development of the agents recently in clinical trial, update on their trial progress, consider reasons for failed efficacy of two agents, and discuss new paradigms in pre-clinical targets for AKI. Agents covered include- QPI-1002, THR-184, BB-3, heme arginate, human recombinant alkaline phosphatase (recAP), ciclosporin A, AB103, levosimendan, AC607 and ABT-719. Expert opinion: Due to the heterogenous nature of AKI, agents with the widest pleiotropic effects on multiple pathophysiological pathways are likely to be most effective. Linking preclinical models to clinical indication and improving AKI definition and diagnosis are key areas for improvement in future clinical trials.

Qnr is a plasmid-encoded and chromosomally determined protein that protects DNA gyrase and topoisomerase IV from inhibition by quinolones. Despite its prevalence worldwide and existence prior to the discovery of quinolones, its native function is not known. Other synthetic compounds and natural products also target bacterial topoisomerases. A number were studied as molecular probes to gain insight into how Qnr acts. Qnr blocked inhibition by synthetic compounds with somewhat quinolone-like structure that target the GyrA subunit, such as the 2-pyridone ABT-719, the quinazoline-2,4-dione PD 0305970, and the spiropyrimidinetrione pyrazinyl-alkynyl-tetrahydroquinoline (PAT), indicating that Qnr is not strictly quinolone specific, but Qnr did not protect against GyrA-targeting simocyclinone D8 despite evidence that both simocyclinone D8 and Qnr affect DNA binding to gyrase. Qnr did not affect the activity of tricyclic pyrimidoindole or pyrazolopyridones, synthetic inhibitors of the GyrB subunit, or nonsynthetic GyrB inhibitors, such as coumermycin A1, novobiocin, gyramide A, or microcin B17.Thus, in this set of compounds the protective activity of Qnr was confined to those that, like quinolones, trap gyrase on DNA in cleaved complexes.