Chagas Disease: Perspectives on the Past and Present and Challenges in Drug Discovery

Abstract

Chagas disease still has no effective treatment option for all of its phases despite being discovered more than 100 years ago. The development of commercial drugs has been stagnating since the 1960s, a fact that sheds light on the question of how drug discovery research has progressed and taken advantage of technological advances. Could it be that technological advances have not yet been sufficient to resolve this issue or is there a lack of protocol, validation and standardization of the data generated by different research teams? This work presents an overview of commercial drugs and those that have been evaluated in studies and clinical trials so far. A brief review is made of recent target-based and phenotypic studies based on the search for molecules with anti-Trypanosoma cruzi action. It also discusses how proteochemometric (PCM) modeling and microcrystal electron diffraction (MicroED) can help in the case of the lack of a 3D protein structure; more specifically, Trypanosoma cruzi carbonic anhydrase.

Structural Insights into Schistosoma mansoni Carbonic Anhydrase (SmCA) Inhibition by Selenoureido-Substituted Benzenesulfonamides

“…The purified recombinant SmCA possesses extremely rapid CO 2 -hydration kinetics too . CA enzymes participate in a wide range of physiologic reactions including respiration, photosynthesis, pH regulation, electrolyte secretion, and many biosynthetic reactions. − In recent years, much effort has been made to develop new CA inhibitors as novel therapeutics to treat neglected tropical diseases and to mitigate the impact of drug resistance that is arising in common anti-parasitic drugs clinically in use. − It is imperative to identify the structural differences between human CAs and parasite CAs in order to develop potent and selective inhibitors as novel anti-infective drugs. Because large differences between the crystal structure of SmCA and the physiologically dominant human isoform hCA II have previously been shown in terms of regional conformation, active-site configuration, and in the length of connections between strands, it is worth speculating that selective SmCA inhibitors can be identified and developed.…”

Immunomodulation for the Treatment of Chronic Chagas Disease Cardiomyopathy: A New Approach to an Old Enemy

“…Chagas disease, caused by Trypanosoma cruzi infection, is a neglected disease classically transmitted to animals and people by hematophagous triatomine vectors ( Santos et al., 2020 ; Mansoldo et al., 2020 ). It represents an important public health problem, affecting around 7 million people worldwide ( WHO, 2021 ).…”

KBE009: A Bestatin-Like Inhibitor of the Trypanosoma cruzi Acidic M17 Aminopeptidase with In Vitro Anti-Trypanosomal Activity

“…The two drugs aVailable for treatment, namely nifurtimox and benznidazole, are partially effective and significantly toxic [8]. They only work in the acute phase of the disease, which usually, unfortunately, goes unnoticed due to the absence of specific symptoms.…”

“…A rational drug design is based on the identification and characterization of new molecular targets. This approach can make a significant contribution to the fight against persistent sicknesses, which are often difficult to treat, as Chagas disease [8]. In this regard, proteases are considered good drug targets [9], as these enzymes are involved in many aspects of the parasite's physiology [10,11].…”