Perspectives for a new drug candidate for Chagas disease therapy

Abstract

Chagas disease (CD), a neglected tropical illness caused by the protozoan Trypanosoma cruzi , affects more than 6 million people mostly in poor areas of Latin America. CD has two phases: an acute, short phase mainly oligosymptomatic followed to the chronic phase, a long-lasting stage that may trigger cardiac and/or digestive disorders and death. Only two old drugs are available and both present low efficacy in the chronic stage, display side effects and are inactive against parasite strains naturally resistant to these nitroderivatives. These shortcomings justify the search for novel therapeutic options considering the target product profile for CD that will be presently reviewed besides briefly revisiting the data on phosphodiesterase inhibitors upon T. cruzi .

Multi-therapeutic strategy targeting parasite and inflammation-related alterations to improve prognosis of chronic Chagas cardiomyopathy: a hypothesis-based approach*

“…To control parasite persistence, patients may benefit of protocols lowering doses of Bz or using short-term administration schemes, to preclude side effects. Certainly, novel drugs targeting parasite biological circuits may offer new opportunities to eliminate infection, (6,46) and even present the possibility of a drug cocktail targeting parasite for CD therapy. Consid-Fig.…”

The Impact of the CTHRSSVVC Peptide Upon Experimental Models of Trypanosoma cruzi Infection

“…CD has two phases, acute and chronic, and since its discovery in 1909 by Carlos Chagas, it poses as a serious public health problem (WHO, 2022). Vaccines are not available and then control and treatment are exclusively related to drug therapy based on two very old pharmacological entities-benznidazole (Bz) and nifurtimox (NF)-introduced in clinical use for more than five decades (Soeiro and de Castro, 2009;Soeiro and de Castro, 2011;Soeiro, 2022). Both nitroderivatives have serious drawbacks including their limited efficacy, especially in the later chronic phase, and severe side effects with discontinuation (about 20%) of treatment (Soeiro and de Castro, 2011;Vieira et al, 2019;de Araujo et al, 2020).…”

“…Different experimental therapeutic approaches have been pursued aiming to find new drug candidates to face this sad scenario. The search includes several strategies such as i) repositioning studies of drugs already available in the market for other illness conditions, ii) identification of new antiparasitic agents using diverse libraries (composed of natural and synthetic products), iii) design and synthesis of new chemical entities selectively directed to molecular targets as well as iv) combined therapy, and v) molecular hybridization (hybrid compounds) combining two molecules (or parts of them) in a single new chemical entity to act on multiple targets of interest (Scarim et al, 2018;Simões-Silva et al, 2019;Soeiro, 2022).…”

“…The knowledge regarding the mechanisms involved in the pathological manifestations of CD has still not been fully gained (Soeiro, 2022). This knowledge could bring relevant contributions to the identification of more selective and complementary therapy for CD.…”

“…This knowledge could bring relevant contributions to the identification of more selective and complementary therapy for CD. In fact, despite being able to control and reduce the parasitic load in the acute phase, the host immune response and triggered inflammation are not able to fully eliminate the infection, and a progressive unbalanced inflammatory response (triggered by residual parasitism) is associated with the deteriorated conditions and may represent an important target for CD therapy (Benvenuti et al, 2017;Soeiro, 2022).…”