Inhibitors of Trypanosoma cruzi Sir2 related protein 1 as potential drugs against Chagas disease

• Published in: PLoS neglected tropical diseases 2018-01, Vol.12 (1), p.e0006180-e0006180
• Main Authors: Gaspar, Luís, Coron, Ross P, KongThoo Lin, Paul, Costa, David M, Perez-Cabezas, Begoña, Tavares, Joana, Roura-Ferrer, Meritxell, Ramos, Isbaal, Ronin, Céline, Major, Louise L, Ciesielski, Fabrice, Pemberton, Iain K, MacDougall, Jane, Ciapetti, Paola, Smith, Terry K, Cordeiro-da-Silva, Anabela
• Format: Article
• Language: English
• Subjects: Amastigotes; Animals; Antiprotozoal Agents - metabolism; Benznidazole; Biology and Life Sciences; Cardiomyopathy; Causes of; Cell cycle; Chagas disease; Chagas Disease - drug therapy; Chagas Disease - parasitology; Chemical kinetics; Disease control; Disease Models, Animal; Diseases; Drug discovery; Drug therapy; Drugs; Enzyme Inhibitors - metabolism; Epimastigotes; Formulations; Funding; Genetic aspects; Health aspects; Heart; Inhibitors; Medicine and Health Sciences; Mice; Morbidity; NAD; Niacinamide - metabolism; Nicotinamide; Parasites; Parasitic diseases; Pharmaceutical sciences; Pharmacokinetics; Pharmacology; Physical Sciences; Physiological aspects; Proteins; Protozoa; Protozoan Proteins - antagonists & inhibitors; Quinolones - metabolism; R&D; Research & development; Sirtuins; Specificity; Spermidine; Spermine - analogs & derivatives; Spermine - metabolism; Substrates; Supervision; Treatment Outcome; Tropical diseases; Trypanosoma cruzi; Trypanosoma cruzi - drug effects; Vector-borne diseases
• ISSN: 1935-2735; 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0006180

Chagas disease remains one of the most neglected diseases in the world despite being the most important parasitic disease in Latin America. The characteristic chronic manifestation of chagasic cardiomyopathy is the region's leading cause of heart-related illness, causing significant mortality and morbidity. Due to the limited available therapeutic options, new drugs are urgently needed to control the disease. Sirtuins, also called Silent information regulator 2 (Sir2) proteins have long been suggested as interesting targets to treat different diseases, including parasitic infections. Recent studies on Trypanosoma cruzi sirtuins have hinted at the possibility to exploit these enzymes as a possible drug targets. In the present work, the T. cruzi Sir2 related protein 1 (TcSir2rp1) is genetically validated as a drug target and biochemically characterized for its NAD+-dependent deacetylase activity and its inhibition by the classic sirtuin inhibitor nicotinamide, as well as by bisnaphthalimidopropyl (BNIP) derivatives, a class of parasite sirtuin inhibitors. BNIPs ability to inhibit TcSir2rp1, and anti-parasitic activity against T. cruzi amastigotes in vitro were investigated. The compound BNIP Spermidine (BNIPSpd) (9), was found to be the most potent inhibitor of TcSir2rp1. Moreover, this compound showed altered trypanocidal activity against TcSir2rp1 overexpressing epimastigotes and anti-parasitic activity similar to the reference drug benznidazole against the medically important amastigotes, while having the highest selectivity index amongst the compounds tested. Unfortunately, BNIPSpd failed to treat a mouse model of Chagas disease, possibly due to its pharmacokinetic profile. Medicinal chemistry modifications of the compound, as well as alternative formulations may improve activity and pharmacokinetics in the future. Additionally, an initial TcSIR2rp1 model in complex with p53 peptide substrate was obtained from low resolution X-ray data (3.5 Å) to gain insight into the potential specificity of the interaction with the BNIP compounds. In conclusion, the search for TcSir2rp1 specific inhibitors may represent a valuable strategy for drug discovery against T. cruzi.