Acarbose presents in vitro and in vivo antileishmanial activity against Leishmania infantum and is a promising therapeutic candidate against visceral leishmaniasis

Abstract

Treatment against visceral leishmaniasis (VL) is mainly hampered by drug toxicity, long treatment regimens and/or high costs. Thus, the identification of novel and low-cost antileishmanial agents is urgent. Acarbose (ACA) is a specific inhibitor of glucosidase-like proteins, which has been used for treating diabetes. In the present study, we show that this molecule also presents in vitro and in vivo specific antileishmanial activity against Leishmania infantum . Results showed an in vitro direct action against L. infantum promastigotes and amastigotes, and low toxicity to mammalian cells. In addition, in vivo experiments performed using free ACA or incorporated in a Pluronic ® F127-based polymeric micelle system called ACA/Mic proved effective for the treatment of L. infantum -infected BALB/c mice. Treated animals presented significant reductions in the parasite load in their spleens, livers, bone marrows and draining lymph nodes when compared to the controls, as well as the development of antileishmanial Th1-type humoral and cellular responses based on high levels of IFN-γ, IL-12, TNF-α, GM-CSF, nitrite and IgG2a isotype antibodies. In addition, ACA or ACA-treated animals suffered from low organ toxicity. Treatment with ACA/Mic outperformed treatments using either Miltefosine or free ACA based on parasitological and immunological evaluations performed one and 15 days post-therapy. In conclusion, data suggest that the ACA/Mic is a potential therapeutic agent against L. infantum and merits further consideration for VL treatment.

TargetingLeishmania infantumMannosyl-oligosaccharide glucosidase with natural products: pH-dependent inhibition explored through computer-aided drug design

“…Due to the promising results obtained in our previous research (Chavez-Fumagalli et al, 2019;Costa et al, 2021), we utilized and modeled MOGS (formerly categorized as a hypothetical protein) as a potential target and receptor in this study to evaluate the effect of NPs (Figure 3A).…”

“…Likewise, Acarbose altered the mitochondrial function of L. infantum , leading to increased reactive oxygen species (ROS) production and lipid accumulation. This alteration induced a specific production of Th1-type cytokines, reducing parasitism in diverse targeted organs (Costa et al, 2021).…”

Mass Spectrometry-Based Metabolomics Revealed Effects of Metronidazole on Giardia duodenalis

“…This metabolite has been used for treating diabetics as a specific inhibitor of glucosidase-like proteins. In addition, it demonstrated in vitro and in vivo antileishmanial activity against Leishmania infantum [ 32 ]. The up-regulated acarbose may have antiparasitic effects in G. duodenalis , similar to the Leishmania parasite.…”

Challenges and Tools for In Vitro Leishmania Exploratory Screening in the Drug Development Process: An Updated Review

“…Although medicine donation programs are multiplying to support the burden of neglected tropical diseases [150] such as leishmaniases, the pharmaceutical industry seems to increasingly restrict its research and development investment to new drug candidates [151]. Alternative options consist of repurposing drugs [152][153][154] or improving existing drugs, such as the gold standard amphotericin B [155]. Nevertheless, research into new drug candidates that are active against Leishmania must not be excluded, especially as methodological tools are becoming increasingly effective.…”