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Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-[beta]-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivox clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model. 10.1126/science.1193225

A versatile antiviral: Dengue virus (DENV) is a mosquito-borne flavivirus that lacks any effective antiviral treatments. There are four serotypes of DENV, all of which can cause disease, including dengue fever, dengue shock syndrome, or dengue hemorrhagic fever. Thus, an antiviral drug needs to be effective against all four serotypes. Here, Moquin et al. identify an inhibitor of the DENV protein NS4B that is effective against all four serotypes in vitro and against DENV-2 in vivo in mice. The authors show that the inhibitor, NITD-688, is well tolerated and has favorable pharmacokinetic properties in rats and dogs and decreased viremia in mice when treated up to 2 days after DENV infection. These findings suggest that NITD-688 is a promising candidate for a DENV antiviral drug. Dengue virus (DENV) is a mosquito-borne flavivirus that poses a threat to public health, yet no antiviral drug is available. We performed a high-throughput phenotypic screen using the Novartis compound library and identified candidate chemical inhibitors of DENV. This chemical series was optimized to improve properties such as anti-DENV potency and solubility. The lead compound, NITD-688, showed strong potency against all four serotypes of DENV and demonstrated excellent oral efficacy in infected AG129 mice. There was a 1.44-log reduction in viremia when mice were treated orally at 30 milligrams per kilogram twice daily for 3 days starting at the time of infection. NITD-688 treatment also resulted in a 1.16-log reduction in viremia when mice were treated 48 hours after infection. Selection of resistance mutations and binding studies with recombinant proteins indicated that the nonstructural protein 4B is the target of NITD-688. Pharmacokinetic studies in rats and dogs showed a long elimination half-life and good oral bioavailability. Extensive in vitro safety profiling along with exploratory rat and dog toxicology studies showed that NITD-688 was well tolerated after 7-day repeat dosing, demonstrating that NITD-688 may be a promising preclinical candidate for the treatment of dengue. [ABSTRACT FROM AUTHOR]

The article presents a study which identified a class of small-molecule mycobactericidal agents, the 4-hydroxy-2 pyridones for the treatment of multidrug resistant tuberculosis (MDR-TB), using phenotypic screening. Topics discussed include identification and validation of the molecular target, activity of the 4-hydroxy-2 pyridones against a panel of drug-resistant TB clinical isolates, and pharmacology of 4-hydroxy-2 pyridones.

Millions who live in Latin America and sub-Saharan Africa are at risk of trypanosomatid infections, which cause Chagas disease and human African trypanosomiasis (HAT). Improved HAT treatments are available, but Chagas disease therapies rely on two nitroheterocycles, which suffer from lengthy drug regimens and safety concerns that cause frequent treatment discontinuation. We performed phenotypic screening against trypanosomes and identified a class of cyanotriazoles (CTs) with potent trypanocidal activity both in vitro and in mouse models of Chagas disease and HAT. Cryo-electron microscopy approaches confirmed that CT compounds acted through selective, irreversible inhibition of trypanosomal topoisomerase II by stabilizing double-stranded DNA:enzyme cleavage complexes. These findings suggest a potential approach toward successful therapeutics for the treatment of Chagas disease.