Drug Discovery and Development for Kinetoplastid Diseases

Abstract

In this article, we review the disease, biology, and biochemistry of kinetoplastids, as well as the new drugs and drug candidates that have entered the clinic in the last decade. We also describe examples of the preclinical exploration of small molecules against various protein targets (e.g. cysteine proteases, the proteasome, and tubulin), as well as cutting‐edge molecular and computational strategies and technologies being brought to bear to discover and develop new antitrypanosomal drugs. For comprehensive descriptions of the disease, biology, and drug therapies prior to 2011, the reader is encouraged to review the article by P.M. Woster that appeared in 2010 in the seventh edition of Burger's Medicinal Chemistry, Drug Discovery, and Development, entitled Antiprotozoal/Antiparasitic Agents.

Screening the Pathogen Box to Discover and Characterize New Cruzain and TbrCatL Inhibitors

“…Available treatments are suboptimal for both diseases. Benznidazole and Nifurtimox, the current chemotherapeutic options for CD, are only effective in the acute phase and are associated with significant adverse effects, which include gastric and neurological disorders [ 3 , 10 , 11 , 12 , 13 ]. Moreover, it was shown that chronic asymptomatic patients have no clinical benefit on their cardiac condition after Benznidazole therapy [ 14 ].…”

Experimental and Computational Study of Aryl-thiosemicarbazones Inhibiting Cruzain Reveals Reversible Inhibition and a Stepwise Mechanism

“…Despite a reduction in mortality and infections, mainly attributed to vector control and an overall improvement in socioeconomic conditions, Chagas disease is estimated to have caused 9490 deaths in 2019, mostly in Latin America . Currently, only two drugs are available for use against Chagas disease: Nifurtimox and Benznidazole, which are efficient mainly in the acute phase. − After the progression of the disease to the indeterminate or chronic phases, no effective treatment is available. Furthermore, Nifurtimox and Benznidazole are associated with serious adverse side effects and long treatment duration (up to 2 months).…”

Structure-Based Optimization of Quinazolines as Cruzain and TbrCATL Inhibitors

“…Two subspecies of Trypanosoma brucei elicit different Human African trypanosomiasis (HAT) patterns: Trypanosoma brucei gambiense causes a slowly progressing disease in western and central Africa, while Trypanosoma brucei rhodesiense induces a more rapid pathology in eastern and southern Africa. − Although five drugs are used for HAT therapy, some have limited efficacy and suffer from drug resistance. − Suramin and pentamidine are used to treat the first-stage disease caused by T. b. rhodesiense and T.…”

“…b. gambiense includes a combination of eflornithine and nifurtimox, whereas melarsoprol, which comes with a risk of severe adverse events, remains the only acceptable option for T. b. rhodesiense . Recently, fexinidazole was approved by the WHO for treatment of first and second stage infection by T.…”

“…cruzi . Moreover, it is recognized by the host as an antigen and modulates the host macrophage response. , Tbr CATL is important for penetration through the blood–brain barrier and is essential for parasite survival. ,, Efforts to develop inhibitors have led to the discovery of many potent chemotypes against both proteases (reviewed in refs , , and ). Recently reported inhibitors include peptidomimetics − and nonpeptidic small molecules that inhibit the enzymes irreversibly or reversibly. − In addition to their efficacy in in vitro assays against trypanosomes, ,,, cysteine protease inhibitors have shown efficacy in mice − and dog models of Chagas disease, and to reduce parasitemia and/or increase survival ,, in mouse models of T.…”