A Single-Blind, Placebo-Controlled, Randomized First Time in Human Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single and Repeat Dose Escalation of GSK932121 in Healthy Adult Subjects

The purpose of this study is to determine if the study drug (antimalarial medication) is safe when given to healthy subjects as a single dose or as repeated doses, to understand the effect of food on single doses of study drug and to determine if the study drug has an effect on other approved medications such as rosiglitazone and rosuvastatin.

开始日期2008-12-11

申办/合作机构

GSK Plc

100 项与 Pfbc1 相关的临床结果

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100 项与 Pfbc1 相关的转化医学

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0 项与 Pfbc1 相关的专利（医药）

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项与 Pfbc1 相关的文献（医药）

2023-02-01·Journal of Bioenergetics and Biomembranes

The evolution of the human mitochondrial bc1 complex- adaptation for reduced rate of superoxide production?

Article

作者: Rottenberg, Hagai

The mitochondrial bc1 complex is a major source of mitochondrial superoxide. While bc1-generated superoxide plays a beneficial signaling role, excess production of superoxide lead to aging and degenerative diseases. The catalytic core of bc1 comprises three peptides -cytochrome b, Fe-S protein, and cytochrome c1. All three core peptides exhibit accelerated evolution in anthropoid primates. It has been suggested that the evolution of cytochrome b in anthropoids was driven by a pressure to reduce the production of superoxide. In humans, the bc1 core peptides exhibit anthropoid-specific substitutions that are clustered near functionally critical sites that may affect the production of superoxide. Here we compare the high-resolution structures of bovine, mouse, sheep and human bc1 to identify structural changes that are associated with human-specific substitutions. Several cytochrome b substitutions in humans alter its interactions with other subunits. Most significantly, there is a cluster of seven substitutions, in cytochrome b, the Fe-S protein, and cytochrome c1 that affect the interactions between these proteins at the tether arm of the Fe-S protein and may alter the rate of ubiquinone oxidation and the rate of superoxide production. Another cluster of substitutions near heme bH and the ubiquinone reduction site, Qi, may affect the rate of ubiquinone reduction and thus alter the rate of superoxide production. These results are compatible with the hypothesis that cytochrome b in humans (and other anthropoid primates) evolve to reduce the rate of production of superoxide thus enabling the exceptional longevity and exceptional cognitive ability of humans.

2022-10-11·ACS Omega

Design of Anti-infectious Agents from Lawsone in a Three-Component Reaction with Aldehydes and Isocyanides

Article

作者: Salina, Elena G. ; Degiacomi, Giulia ; Vendier, Laure ; Benoit-Vical, Françoise ; Bijani, Christian ; Anne Robert ; García-Sosa, Alfonso T. ; Loiseau, Philippe M. ; Baltas, Michel ; Koumpoura, Christina L. ; Buroni, Silvia ; Cojean, Sandrine ; Nguyen, Michel

The first effective synthetic approach to naphthofuroquinones via a reaction involving lawsone, various aldehydes, and three isocyanides under microwave irradiation afforded derivatives in moderate to good yields. In addition, for less-reactive aldehydes, two naphtho-enaminodione quinones were obtained for the first time, as result of condensation between lawsone and isocyanides. X-ray structure determination for 9 and 2D-NMR spectra of 28 confirmed the obtained structures. All compounds were evaluated for their anti-infectious activities against Plasmodium falciparum, Leishmania donovani, and Mycobacterium tuberculosis. Among the naphthofuroquinone series, 17 exhibited comparatively the best activity against P. falciparum (IC₅₀ = 2.5 μM) and M. tuberculosis (MIC = 9 μM) with better (P. falciparum) or equivalent (M. tuberculosis) values to already-known naphthofuroquinone compounds. Among the two naphtho-enaminodione quinones, 28 exhibited a moderate activity against P. falciparum with a good selectivity index (SI > 36) while also a very high potency against L. donovani (IC₅₀ = 3.5 μM and SI > 28), rendering it very competitive to the reference drug miltefosine. All compounds were studied through molecular modeling on their potential targets for P. falciparum, Pfbc1, and PfDHODH, where 17 showed the most favorable interactions.

2017-04-01·Memórias do Instituto Oswaldo Cruz4区 · 医学

Insights into cytochrome bc1 complex binding mode of antimalarial 2-hydroxy-1,4-naphthoquinones through molecular modelling

4区 · 医学

ArticleOA

作者: Ferreira, Sabrina Baptista ; Sodero, Ana Carolina Rennó ; Pascutti, Pedro Geraldo ; Ferreira, Vitor Francisco ; Torres, Pedro Henrique Monteiro ; Silva, Floriano Paes ; Abrahim-Vieira, Bárbara ; Rocha, David Rodrigues da ; Garcia, Célia Rs

BACKGROUNDMalaria persists as a major public health problem. Atovaquone is a drug that inhibits the respiratory chain of Plasmodium falciparum, but with serious limitations like known resistance, low bioavailability and high plasma protein binding.OBJECTIVESThe aim of this work was to perform molecular modelling studies of 2-hydroxy-1,4-naphthoquinones analogues of atovaquone on the Qo site of P. falciparum cytochrome bc1 complex (Pfbc1) to suggest structural modifications that could improve their antimalarial activity.METHODSWe have built the homology model of the cytochrome b (CYB) and Rieske iron-sulfur protein (ISP) subunits from Pfbc1 and performed the molecular docking of 41 2-hydroxy-1,4-naphthoquinones with known in vitro antimalarial activity and predicted to act on this target.FINDINGSResults suggest that large hydrophobic R2 substituents may be important for filling the deep hydrophobic Qo site pocket. Moreover, our analysis indicates that the H-donor 2-hydroxyl group may not be crucial for efficient binding and inhibition of Pfbc1 by these atovaquone analogues. The C1 carbonyl group (H-acceptor) is more frequently involved in the important hydrogen bonding interaction with His152 of the Rieske ISP subunit.MAIN CONCLUSIONSAdditional interactions involving residues such as Ile258 and residues required for efficient catalysis (e.g., Glu261) could be explored in drug design to avoid development of drug resistance by the parasite.