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.

KEYWORDS:

• Drug development
• cytochrome bc₁
• mitochondrion
• respiration
• structure–activity relationship
• small molecule
• Toxoplasma gondii

Article highlights

• The T. gondii cytochrome bc₁ is a viable drug target demonstrated by both the clinical use of atovaquone and the discovery of structurally diverse cytochrome bc₁ inhibitors.

• Cytochrome bc₁ inhibitors in preclinical development have improved potency and greater selectivity for T. gondii cytochrome bc₁ over mammalian bc₁ relative to atovaquone.

• Structure-activity-relationship analysis of cytochrome bc₁ inhibitors has identified structural features that determine Q_o or Q_i site targeting of cytochrome bc₁.

• This review discusses the potency, efficacy, mechanism, and toxicity of six chemotypes of cytochrome bc₁ inhibitors.

• Many preclinical cytochrome bc₁ inhibitors are remarkably potent inhibitors of T. gondii proliferation, demonstrating that targeting this enzyme complex holds great promise for improved therapies for toxoplasmosis.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

The authors disclose that they are listed as inventors on multiple patents related to the endochin-like quinolones presented in this review.

Additional information

Funding

This paper was funded by the Department of Veterans Affairs (IK2BX004940, I01BX004522) and the Department of Defense (PR181134, NIH RO1AI141412).