Dados do Trabalho

Título

Assessing the pharmacological potential of artemisinin hybrid-based drugs for the treatment of malaria

Introdução

Artemisinins (ART) is a class of antimalarial endoperoxides that were game-changing drugs in the therapy; however, has emerging resistant parasites to this treatment. The main hallmarks of this resistance are a delayed clearance phenotype (DCP) and single-nucleotide polymorphisms in the Pfk13 gene. An approach to overcoming DCP is extending the duration of ACT therapy. In this context, hybrid-based drugs are a promising alternative that can play a dual role, acting as a chemical bridge necessary for the conjugation of pharmacophoric groups and also introducing a structural conformation with no immediate exposition to heme, warranting the potential of hybrids to present an extended half-life in comparison to parental ART.

Objetivo (s)

To characterize the susceptibility of ART-sensitive or resistant asexual blood-stage parasites for hybrids (1) and (2) and to correlate the phenotype-based activity with chemical stability and the long-lasting duration of antiparasitic activity.

Material e Métodos

Hybrids were evaluated in vitro against different strains of P. falciparum at the asexual blood stages, and at different times to evaluate their speed of action. In an erythrocyte culture, we evaluated the hybrid stability over time. Additionally, a recrudescence assay, ring-stage survival assay (RSA) and quiescent-stage assay (QSA) were performed and the antiparasitic potency was evaluated against sensitive or resistant P. falciparum strains.

Resultados e Conclusão

Hybrids showed a parasite growth reduction as high as DHA against P. falciparum. Also, rings and trophozoites are the maximally susceptible stages for hybrids. In the RSA, the activity of DHA or hybrid (1) decreases while hybrid (2) activity persists; consistent with RSA data, IC50 values shift from continuous drug exposure in comparison to a short-pulse treatment. Hybrid (2) has metabolic stability in liver microsomes similar to ARTs, but it has superior chemical stability in erythrocytes, being higher than DHA or hybrid (1). Against ART-derived quiescent parasites, the antimalarial activity for hybrid (2) is relatively low. Taken together, the hybrids can display a summation of activity when co-exposure to other antimalarials, and based on this, we propose that the hybrid may be suitable for replacing ART in artemisinin-based combination therapy (ACT).

Palavras-chave

Plasmodium, drug therapy, artemisinins; phenotype-based activity, slow-clearing infection, heme activation.

Agradecimentos

CAPES, CNPq, Deutsche Forschungsgemeinschaft, Fondazione Cariplo, Fondation pour la Recherche
754 Médicale