Dataset Information

Structure-activity relationships of Toxoplasma gondii cytochrome bc₁ inhibitors.

ABSTRACT:

Introduction

Toxoplasma gondii is a prolific apicomplexan parasite that infects human and nonhuman animals worldwide and can cause severe brain and eye disease. Safer, more effective therapies for toxoplasmosis are needed. Cytochrome bc₁ inhibitors are remarkably effective against toxoplasmosis and other apicomplexan-caused diseases.

Areas covered

This work reviews T. gondii cytochrome bc₁ inhibitors. Emphasis is placed on the structure-activity relationships of these inhibitors with regard to efficacy, pharmacokinetics, selectivity of T. gondii cytochrome bc₁ over host, safety, and potential therapeutic strategies.

Expert opinion

Cytochrome bc₁ inhibitors are highly promising compounds for toxoplasmosis that have been effective in clinical and preclinical studies. Clinical experience with atovaquone previously validated cytochrome bc₁ as a tractable drug target and, over the past decade, optimization of cytochrome bc₁ inhibitors has resulted in improved bioavailability, metabolic stability, potency, blood-brain barrier penetration, and selectivity for the T. gondii cytochrome bc₁ over the mammalian bc₁. Recent studies have demonstrated preclinical safety, identified novel therapeutic strategies for toxoplasmosis using synergistic combinations or long-acting administration and provided insight into their role in chronic infection. This research has identified drug candidates that are more effective than clinically used drugs in preclinical measures of efficacy.

SUBMITTER: Alday PH

PROVIDER: S-EPMC9561756 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Publications

Structure-activity relationships of <i>Toxoplasma gondii</i> cytochrome <i>bc</i><sub>1</sub> inhibitors.

Alday P Holland PH Nilsen Aaron A Doggett J Stone JS

Expert opinion on drug discovery 20220808 9

<h4>Introduction</h4><i>Toxoplasma gondii</i> is a prolific apicomplexan parasite that infects human and nonhuman animals worldwide and can cause severe brain and eye disease. Safer, more effective therapies for toxoplasmosis are needed. Cytochrome <i>bc</i><sub>1</sub> inhibitors are remarkably effective against toxoplasmosis and other apicomplexan-caused diseases.<h4>Areas covered</h4>This work reviews <i>T. gondii</i> cytochrome <i>bc</i><sub>1</sub> inhibitors. Emphasis is placed on the stru ...[more]

PMID: 35772172

Similar Datasets

Project description:Aspects of the crystal structures of the hetero-oligomeric cytochrome bc(1) and b(6)f ("bc") complexes relevant to their electron/proton transfer function and the associated redox reactions of the lipophilic quinones are discussed. Differences between the b(6)f and bc(1) complexes are emphasized. The cytochrome bc(1) and b(6)f dimeric complexes diverge in structure from a core of subunits that coordinate redox groups consisting of two bis-histidine coordinated hemes, a heme b(n) and b(p) on the electrochemically negative (n) and positive (p) sides of the complex, the high potential [2Fe-2S] cluster and c-type heme at the p-side aqueous interface and aqueous phase, respectively, and quinone/quinol binding sites on the n- and p-sides of the complex. The bc(1) and b(6)f complexes diverge in subunit composition and structure away from this core. b(6)f Also contains additional prosthetic groups including a c-type heme c(n) on the n-side, and a chlorophyll a and β-carotene. Common structure aspects; functions of the symmetric dimer. (I) Quinone exchange with the bilayer. An inter-monomer protein-free cavity of approximately 30Å along the membrane normal×25Å (central inter-monomer distance)×15Å (depth in the center), is common to both bc(1) and b(6)f complexes, providing a niche in which the lipophilic quinone/quinol (Q/QH(2)) can be exchanged with the membrane bilayer. (II) Electron transfer. The dimeric structure and the proximity of the two hemes b(p) on the electrochemically positive side of the complex in the two monomer units allow the possibility of two alternate routes of electron transfer across the complex from heme b(p) to b(n): intra-monomer and inter-monomer involving electron cross-over between the two hemes b(p). A structure-based summary of inter-heme distances in seven bc complexes, representing mitochondrial, chromatophore, cyanobacterial, and algal sources, indicates that, based on the distance parameter, the intra-monomer pathway would be favored kinetically. (III) Separation of quinone binding sites. A consequence of the dimer structure and the position of the Q/QH(2) binding sites is that the p-side QH(2) oxidation and n-side Q reduction sites are each well separated. Therefore, in the event of an overlap in residence time by QH(2) or Q molecules at the two oxidation or reduction sites, their spatial separation would result in minimal steric interference between extended Q or QH(2) isoprenoid chains. (IV) Trans-membrane QH(2)/Q transfer. (i) n/p-side QH(2)/Q transfer may be hindered by lipid acyl chains; (ii) the shorter less hindered inter-monomer pathway across the complex would not pass through the center of the cavity, as inferred from the n-side antimycin site on one monomer and the p-side stigmatellin site on the other residing on the same surface of the complex. (V) Narrow p-side portal for QH(2)/Q passage. The [2Fe-2S] cluster that serves as oxidant, and whose histidine ligand serves as a H(+) acceptor in the oxidation of QH(2), is connected to the inter-monomer cavity by a narrow extended portal, which is also occupied in the b(6)f complex by the 20 carbon phytyl chain of the bound chlorophyll.

Dataset Information

Structure-activity relationships of Toxoplasma gondii cytochrome bc₁ inhibitors.

Introduction

Areas covered

Expert opinion

Publications

Structure-activity relationships of <i>Toxoplasma gondii</i> cytochrome <i>bc</i><sub>1</sub> inhibitors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Structure-activity relationships of Toxoplasma gondii cytochrome bc1 inhibitors.

Introduction

Areas covered

Expert opinion

Publications

Structure-activity relationships of <i>Toxoplasma gondii</i> cytochrome <i>bc</i><sub>1</sub> inhibitors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Structure-activity relationships of Toxoplasma gondii cytochrome bc₁ inhibitors.