Advances in preclinical approaches to Chagas disease drug discovery

Villalta, Fernando; Rachakonda, Girish

doi:10.1080/17460441.2019.1652593

Cited by 60 publications

(48 citation statements)

References 143 publications

(178 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Infective trypomastigotes and intracellular replicative amastigotes are the clinically relevant life-cycle stages of T. cruzi that are targets for drug intervention [ 57 ]. Briefly, non-dividing T. cruzi metacyclic trypomastigotes are transmitted to humans in the feces of infected triatomine bugs at the bite site of these hematophagous insects.…”

Section: Trypanosomatids′ Life Cycle In the Context Of In Vitro Scmentioning

confidence: 99%

“…Despite many efforts, only two compounds, benznidazole (since 1972) and nifurtimox (since 1967), are currently used for the treatment of certain forms of Chagas disease [ 59 ]. Markedly, drug discovery in T. cruzi is handicapped by the small number of well-established targets (e.g., the sterol biosynthetic pathway, cruzipain, cytochrome b, trypanothione reductase, cyclophilin, or carbonic anhydrases [ 57 ]), which explains the wide use of phenotypic approaches that have become the main pillar of Chagas R&D [ 60 ]. Drug screening against T. cruzi can be performed in cell-free axenic amastigotes and epimastigotes, as well as in intracellular amastigotes, with similar advantages and caveats to those previously discussed for Leishmania .…”

Section: Trypanosomatids′ Life Cycle In the Context Of In Vitro Scmentioning

confidence: 99%

See 1 more Smart Citation

Of Drugs and Trypanosomatids: New Tools and Knowledge to Reduce Bottlenecks in Drug Discovery

Bhattacharya

Corbeil

Monte-Neto

et al. 2020

Genes

View full text Add to dashboard Cite

Leishmaniasis (Leishmania species), sleeping sickness (Trypanosoma brucei), and Chagas disease (Trypanosoma cruzi) are devastating and globally spread diseases caused by trypanosomatid parasites. At present, drugs for treating trypanosomatid diseases are far from ideal due to host toxicity, elevated cost, limited access, and increasing rates of drug resistance. Technological advances in parasitology, chemistry, and genomics have unlocked new possibilities for novel drug concepts and compound screening technologies that were previously inaccessible. In this perspective, we discuss current models used in drug-discovery cascades targeting trypanosomatids (from in vitro to in vivo approaches), their use and limitations in a biological context, as well as different examples of recently discovered lead compounds.

show abstract

Section: Trypanosomatids′ Life Cycle In the Context Of In Vitro Scmentioning

confidence: 99%

Section: Trypanosomatids′ Life Cycle In the Context Of In Vitro Scmentioning

confidence: 99%

Of Drugs and Trypanosomatids: New Tools and Knowledge to Reduce Bottlenecks in Drug Discovery

Bhattacharya

Corbeil

Monte-Neto

et al. 2020

Genes

View full text Add to dashboard Cite

show abstract

“…In the acute phase, the adipose tissue appears to be the major reservoir of recurrence in mice under posaconazole therapy. Inadequate choice of the dose at clinical trials and emergence of azole-resistant parasites should also be considered as possible explanations to the failure at the clinical studies (Campos et al, 2017;Villalta and Rachakonda, 2019). E-1224 (a prodrug of ravuconazole) is another azole being investigated as potential therapy for Chagas (Diniz et al, 2018).…”

Section: Chagas Disease Treatmentmentioning

confidence: 99%

Trypanosomatid-Caused Conditions: State of the Art of Therapeutics and Potential Applications of Lipid-Based Nanocarriers

Muraca¹,

Berti

Sbaraglini³

et al. 2020

Front. Chem.

View full text Add to dashboard Cite

Trypanosomatid-caused conditions (African trypanosomiasis, Chagas disease, and leishmaniasis) are neglected tropical infectious diseases that mainly affect socioeconomically vulnerable populations. The available therapeutics display substantial limitations, among them limited efficacy, safety issues, drug resistance, and, in some cases, inconvenient routes of administration, which made the scenarios with insufficient health infrastructure settings inconvenient. Pharmaceutical nanocarriers may provide solutions to some of these obstacles, improving the efficacy–safety balance and tolerability to therapeutic interventions. Here, we overview the state of the art of therapeutics for trypanosomatid-caused diseases (including approved drugs and drugs undergoing clinical trials) and the literature on nanolipid pharmaceutical carriers encapsulating approved and non-approved drugs for these diseases. Numerous studies have focused on the obtention and preclinical assessment of lipid nanocarriers, particularly those addressing the two currently most challenging trypanosomatid-caused diseases, Chagas disease, and leishmaniasis. In general, in vitro and in vivo studies suggest that delivering the drugs using such type of nanocarriers could improve the efficacy–safety balance, diminishing cytotoxicity and organ toxicity, especially in leishmaniasis. This constitutes a very relevant outcome, as it opens the possibility to extended treatment regimens and improved compliance. Despite these advances, last-generation nanosystems, such as targeted nanocarriers and hybrid systems, have still not been extensively explored in the field of trypanosomatid-caused conditions and represent promising opportunities for future developments. The potential use of nanotechnology in extended, well-tolerated drug regimens is particularly interesting in the light of recent descriptions of quiescent/dormant stages of Leishmania and Trypanosoma cruzi, which have been linked to therapeutic failure.

show abstract

“…Several targets are being researched for the development of new drug candidates against Chagas disease [56]. Cruzain and Tc80 proteinase deserve to be highlighted here.…”

Section: Chagas Diseasementioning

confidence: 99%

Neglected tropical diseases and infectious illnesses: potential targeted peptides employed as hits compounds in drug design

Silva

Santos

Miranda

et al. 2020

Journal of Drug Targeting

View full text Add to dashboard Cite

Neglected Tropical Diseases (NTDs) and infectious illnesses, such as malaria, tuberculosis and Zika fever, represent a major public health concern in many countries and regions worldwide, especially in developing ones. They cause thousands of deaths per year, and certainly compromise the life of affected patients. The drugs available for therapy are toxic, have considerable adverse effects, and are obsolete, especially with respect to resistance. In this context, targeted peptides are considered promising in the design of new drugs, since they have specific action and reduced toxicity. Indeed, there is a rising interest in these targeted compounds within the pharmaceutical industry, proving their importance to the Pharmaceutical Sciences field. Many have been approved by the Food and Drug Administration (FDA) to be used as medicines, plus there are more than 300 peptides currently in clinical trials. The main purpose of this review is to show the most promising potential targeted peptides acting as hits molecules in NTDs and other infectious illnesses. We hope to contribute to the discovery of medicines in this relatively neglected area, which will be extremely useful in improving the health of many suffering people.

show abstract

Advances in preclinical approaches to Chagas disease drug discovery

Cited by 60 publications

References 143 publications

Of Drugs and Trypanosomatids: New Tools and Knowledge to Reduce Bottlenecks in Drug Discovery

Of Drugs and Trypanosomatids: New Tools and Knowledge to Reduce Bottlenecks in Drug Discovery

Trypanosomatid-Caused Conditions: State of the Art of Therapeutics and Potential Applications of Lipid-Based Nanocarriers

Neglected tropical diseases and infectious illnesses: potential targeted peptides employed as hits compounds in drug design

Contact Info

Product

Resources

About