Novel Drugs Targeting the c-Ring of the F₁F_O-ATP Synthase

Title:Novel Drugs Targeting the c-Ring of the F₁F_O-ATP Synthase

Volume: 16 Issue: 10

Author(s): Alessandra Pagliarani, S. Nesci and V. Ventrella

Affiliation:

Keywords: ATP synthase, c-ring, diarylquinolines, drug target, enzyme inhibition, macrolides, organotins.

Abstract: Increasing evidence highlights the role of the ATP synthase/hydrolase, also known as F₁F_O-complex, as key molecular and enzymatic switch between cell life and death, thus increasing the enzyme attractiveness as drug target in pharmacology. Being inhibition of ATP production usually linked to antiproliferative properties, drugs targeting the enzyme complex have been mainly considered to fight pathogen parasites and cancer. In recent years, a number of natural macrolides, produced by bacterial fermentation and structurally related to the classical enzyme inhibitor oligomycin, have been shown to bind to the membrane-embedded F_O sector and to inhibit the enzyme complex by an oligomycin-like mechanism, namely by interacting with the c-ring. Other than natural macrolide antibiotics, which display variegated inhibition power on different F₁F_O-complexes, synthetic compounds from the diarylquinoline and organotin families also target the c-ring and strongly inhibit the enzyme. Bioinformatic insights address drug design to target F_O subunits. Additionally, the possible modulation of the drug inhibition power, by amino acid substitutions or post-translational modifications of c-subunits, adds further interest to the target. The present survey on compounds targeting the c-ring and bi-directionally blocking the transmembrane proton flux which drives ATP synthesis/hydrolysis, discloses new therapeutic options to fight cancer and infections sustained by therapeutically recalcitrant microorganisms. Additionally, c-ring targeting compounds may constitute new tools to eradicate undesired biofilms and to address at the molecular level the therapy of mammalian diseases linked to mitochondrial dysfunctions. In summary, studies on the only partially known molecular interactions within the c-ring of the F₁F_O-complex may renew hope to counteract mammalian diseases.

Cite this article as:

Pagliarani Alessandra, Nesci S. and Ventrella V., Novel Drugs Targeting the c-Ring of the F₁F_O-ATP Synthase, Mini-Reviews in Medicinal Chemistry 2016; 16 (10) . https://dx.doi.org/10.2174/1389557516666160211120955