In This Issue pubs.acs.org/journal/aidcbc
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A HEPATITIS B INHIBITOR THAT AFFECTS CAPSID FORMATION
with studies in HAT mouse models. Furthermore, the original lead compound was shown to bind the T. brucei methionyl-tRNA synthetase, and its mechanism of action against the enzyme was elucidated. The research study reported by Devine et al. offers important contributions to the development of alternative drugs to combat HAT.
■ Hepatitis B is an infectious disease caused by the hepatitis B virus (HBV) that is spread through contact with bodily fluids. Once inside the body, the virus attacks the liver. Chronic HBV infection affects several million people worldwide and is linked to liver cirrhosis and liver cancer. Current treatment efforts face various obstacles, including low response rates and the emergence of drug resistance. Taking into consideration that the HBV viral capsid plays an important role in DNA replication, Lu et al. (DOI: 10.1021/ acsinfecdis.6b00159) set out to identify potential inhibitors of this process. High-throughput screening and mechanistic studies led to the discovery of a compound with modest activity against the virus. Through lead optimization, a pyridazinone derivative was obtained that exhibited several desirable traits, including potent antiviral activity, while maintaining the same mechanism of action as the original lead compound that involves targeting viral capsid formation. This research may lead to the development of novel therapeutics for HBV.
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Tropical theileriosis is a bovine disease caused by the Protozoa Theileria annulata and poses a significant economic burden. The parasite affects leukocytes and subsequently promotes cancerous cell growth. Infected leukocytes convert glucose into lactate instead of utilizing oxidative glycolysis, which is known as the Warburg effect and is often observed in proliferating cells, including cancer cells. In this issue, Haidar et al. (DOI: 10.1021/acsinfecdis.6b00180) investigated whether disruption of the association between hexokinase 2 (HK2), a glycolytic enzyme that converts glucose into glucose-6-phosphate, and BAD, a glycolytic regulator protein, would prevent initiation of Warburg glycolysis and thus cell proliferation. Because the HK2 recruitment to BAD is contingent on phosphorylation of a serine residue in BAD, the authors examined the effect of a cellpenetrating nonphosphorylating peptide that acts as a BAD substrate. The authors demonstrated that this peptide disrupts HK2/BAD association and subsequently restores oxidative glycolysis in affected cells, which controls their proliferation. This research shows that disruption of BAD protein phosphorylation is a potential avenue for the treatment of tropical theileriosis and cancer.
TOWARD NOVEL THERAPEUTICS FOR SLEEPING SICKNESS
Human African trypanosomiasis (HAT), also known as sleeping sickness, is classified as a neglected tropical disease. It is caused by two subspecies of Trypanosoma brucei and can lead to death in the absence of treatment. Current therapeutic options are limited by their efficacy and toxicity. Herein, Devine et al. (DOI: 10.1021/acsinfecdis.6b00202) describe their results from a study that focused on developing a library of analogues from a trypanocidal compound previously identified via high-throughput screening. The authors performed structure−activity relationship (SAR) investigations with the library members and sought to enhance central nervous system exposure of the original compound. The activity of the molecules against T. brucei is presented along © 2017 American Chemical Society
SUPPRESSING TROPICAL THEILERIOSIS VIA INHIBITION OF WARBURG GLYCOLYSIS
Received: February 22, 2017 Published: March 10, 2017 182
DOI: 10.1021/acsinfecdis.7b00026 ACS Infect. Dis. 2017, 3, 182−182
