Selective Inhibition of the Mitochondrial Permeability Transition Pore Protects against Neurodegeneration in Experimental Multiple Sclerosis.

The mitochondrial permeability transition pore is a recognized drug target for neurodegenerative conditions such as multiple sclerosis and for ischemia-reperfusion injury in the brain and heart. The peptidylprolyl isomerase, cyclophilin D (CypD, PPIF), is a positive regulator of the pore, and genetic down-regulation or knock-out improves outcomes in disease models. Current inhibitors of peptidylprolyl isomerases show no selectivity between the tightly conserved cyclophilin paralogs and exhibit significant off-target effects, immunosuppression, and toxicity. We therefore designed and synthesized a new mitochondrially targeted CypD inhibitor, JW47, using a quinolinium cation tethered to cyclosporine. X-ray analysis was used to validate the design concept, and biological evaluation revealed selective cellular inhibition of CypD and the permeability transition pore with reduced cellular toxicity compared with cyclosporine. In an experimental autoimmune encephalomyelitis disease model of neurodegeneration in multiple sclerosis, JW47 demonstrated significant protection of axons and improved motor assessments with minimal immunosuppression. These findings suggest that selective CypD inhibition may represent a viable therapeutic strategy for MS and identify quinolinium as a mitochondrial targeting group for in vivo use.

Evaluation of Antitrypanosomal Dihydroquinolines for Hepatotoxicity, Mutagenicity, and Methemoglobin Formation In Vitro.

N1-Benzylated dihydroquinolin-6-ols and their corresponding esters display exceptional activity against African trypanosomes in vitro, and administration of members of this class of compounds to trypanosome-infected mice results in cures in a first-stage African trypanosomiasis model. Since a quinone imine intermediate has been implicated in the antiparasitic mechanism of action of these compounds, evaluation of the hepatotoxic, mutagenic, and methemoglobin-promoting effects of these agents was performed. 1-Benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-ol hydrochloride and 1-benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-yl acetate showed outstanding in vitro selectivity for Trypanosoma brucei compared to the HepG2, Hep3B, Huh7, and PLC5 hepatocyte cell lines. 1-Benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-ol hydrochloride and 1-(2-methoxybenzyl)-1,2-dihydro-2,2,4-trimethylquinolin-6-yl acetate were not mutagenic when screened in the Ames assay, with or without metabolic activation. The latter 2 compounds promoted time- and dose-dependent formation of methemoglobin when incubated in whole human blood, but such levels were below those typically required to produce symptoms of methemoglobinemia in humans. Although compounds capable of quinone imine formation require careful evaluation, these in vitro studies indicate that antitrypanosomal dihydroquinolines merit further study as drug candidates against the neglected tropical disease human African trypanosomiasis.

Targeting RNA-protein interactions within the human immunodeficiency virus type 1 lifecycle.

RNA-protein interactions are vital throughout the HIV-1 life cycle for the successful production of infectious virus particles. One such essential RNA-protein interaction occurs between the full-length genomic viral RNA and the major structural protein of the virus. The initial interaction is between the Gag polyprotein and the viral RNA packaging signal (psi or Ψ), a highly conserved RNA structural element within the 5'-UTR of the HIV-1 genome, which has gained attention as a potential therapeutic target. Here, we report the application of a target-based assay to identify small molecules, which modulate the interaction between Gag and Ψ. We then demonstrate that one such molecule exhibits potent inhibitory activity in a viral replication assay. The mode of binding of the lead molecules to the RNA target was characterized by ¹H NMR spectroscopy.

Beneficial effect of macrophage activating agent NK-4 on Thai HIV-infected patients.

BACKGROUND: We examined the effect of NK-4 (4,4'-[3-[2-(1-ethyl-4(1H)-quinolinylidene) ethylidene] propenylene] bis(-ethylquinolinium iodide)) on the clinical course of Thai HIV-infected patients receiving antiretroviral drugs. PATIENTS AND METHODS: Twelve subjects with CD4 count < 500/mm3 were enrolled to receive 0.5 mg of NK-4 orally once daily for 8 weeks and then twice daily during the follow-up. RESULTS: Most patients showed vitality, increased appetite, stable body-weight, increased CD4 counts and no serious adverse effects due to viral load. We suggest that the increased CD4 counts are due to the macrophage activating effect of NK-4. The patients with increased CD4 counts showed lower alpha-N-acetylgalactosaminidase (alpha-NaGalase) activity than those with decreased CD4 counts. CONCLUSION: These results suggest that the macrophage activating agent NK-4, as an inexpensive and safe drug for HIV-infected patients, may play a beneficial role in the clinical treatment of HIV-infected patients.

Therapeutic effects of some antihaematozoal drugs against Haemoproteus columbae in domestic pigeons.

Three antihaematozoal drugs were tested for the treatment of pigeons naturally infected with Haemoproteus columbae. Butalex (Buparvaquone) was found effective against the parasite either by using the recommended dose (R. D.) or the double (D. D.) dosis. The R. D. of Berenil (Diminazene aceturate) was not effective while the D. D. reduced the number of gametocytes circulating in the infected blood. Triquine was found very toxic to the pigeons both the R. D. and the D. D.

Microvascular response to local application of dequalinium chloride. A vital microscopical study of hamster's cheek pouch and a microangiographic study of rabbit's ear.

Dequalinium chloride is a topical antiseptic, whose use may be attended by skin necrosis. Since microcirculatory changes are an early and distinct manifestation of tissue injury, the tissue damaging effect of dequalinium chloride on the microcirculation was examined. The immediate vascular reactions were studied by vital microscopy, of the hamster cheek pouch and the late effects were visualized by microangiography of the rabbit ear. An aqueous solution of dequalinium chloride in concentrations well below those used in clinical practice induced severe microcirculatory disturbances.