Abstract
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.
Highlights
Chagas disease, caused by the protozoan Trypanosoma cruzi, remains one of the most prevalent and neglected diseases in the world [1] and is the parasitic disease with the highest socio-economic burden in Latin America [2, 3]
Trypanosoma cruzi is a protozoan parasite belonging to the Kinetoplastida class responsible for Chagas disease, a neglected tropical illness that affects an estimated 6 to 8 million people in Latin America and some Southern regions of the USA, with another 25 million at risk of acquiring the disease and a death toll of 12,000 every year
We evaluate the potential of a Trypanosoma cruzi sirtuin protein as a novel drug target and its inhibition by novel members of a known class of sirtuin compound inhibitors
Summary
Chagas disease, caused by the protozoan Trypanosoma cruzi, remains one of the most prevalent and neglected diseases in the world [1] and is the parasitic disease with the highest socio-economic burden in Latin America [2, 3]. With no available vaccine for Chagas disease therapies rely upon two drugs introduced more than 40 years ago: benznidazole and nifurtimox. These drugs are far from ideal because of their many toxic side-effects and the requirement of long periods of administration [4, 9, 10]. The recent failure in clinical trials of two of these drugs, posaconazole and E1224, has exposed the fragilities of the chemotherapeutic pipeline and reinforced the need for constant drug discovery efforts to find novel alternative targets and therapies [12,13,14]
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