Lopinavir, an HIV-1 peptidase inhibitor, induces alteration on the lipid metabolism of<i>Leishmania amazonensis</i>promastigotes

Rebello, Karina M.; Andrade-Neto, Valter Viana; Zuma, Aline Araújo; Motta, Maria Cristina M.; Gomes, Cláudia R. B.; Souza, Marcus V. N. de; Atella, Geórgia C.; Branquinha, Marta H.; Santos, André Luis Souza dos; Torres-Santos, Eduardo Caio; d’Avila-Levy, Claudia M.

doi:10.1017/s0031182018000823

Cited by 12 publications

(10 citation statements)

References 56 publications

(68 reference statements)

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“…In addition, drugs that act synergistically on different points of the same pathway represent an attractive strategy for antimicrobial chemotherapy (Roberts et al, 2003; Andrade-Neto et al, 2016). In this sense, our group showed that LPV also alters the lipid composition on L. amazonensis , mainly interfering in sterol composition and causing a pronounced accumulation of cholesterol-ester in treated parasites (Rebello et al, 2018). Although the intracellular target or death mechanism of the HIV-PIs are not totally elucidated in trypanosomatids, it is also likely that they interact and inhibit trypanosomatids aspartyl peptidases (Santos et al, 2013; Castilho et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Miltefosine-Lopinavir Combination Therapy Against Leishmania infantum Infection: In vitro and in vivo Approaches

Rebello

Andrade-Neto

Gomes

et al. 2019

Front. Cell. Infect. Microbiol.

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Concurrently, leishmaniasis and AIDS are global public health issues and the overlap between these diseases adds additional treats to the management of co-infected patients. Lopinavir (LPV) has a well characterized anti-HIV and leishmanicidal action, and to analyze its combined action with miltefosine (MFS) could help to envisage strategies to the management of co-infected patients. Here, we evaluate the interaction between LPV and MFS against Leishmania infantum infection by in vitro and in vivo approaches. The effect of the compounds alone or in association was assessed for 72 h in mouse peritoneal macrophages infected with L. infantum by the determination of the IC 50 s and FICIs. Subsequently, mice were orally treated twice daily during 5 days with the compounds alone or in association and evaluated after 30 days. The in vitro assays revealed an IC 50 of 0.24 μM and 9.89 μM of MFS and LPV, respectively, and an additive effect of the compounds (FICI 1.28). The in vivo assays revealed that LPV alone reduced the parasite load in the spleen and liver by 52 and 40%, respectively. The combined treatment of infected BALB/c mice revealed that the compounds alone required at least two times higher doses than when administered in association to virtually eliminate the parasite. Mice plasma biochemical parameters assessed revealed that the combined therapy did not present any relevant hepatotoxicity. In conclusion, the association of MFS with LPV allowed a reduction in each compound concentration to achieve the same outcome in the treatment of visceral leishmaniasis. Although a pronounced synergistic effect was not evidenced, it does not discard that such combination could be useful in humans co-infected with HIV and Leishmania parasites.

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Section: Discussionmentioning

confidence: 99%

Miltefosine-Lopinavir Combination Therapy Against Leishmania infantum Infection: In vitro and in vivo Approaches

Rebello

Andrade-Neto

Gomes

et al. 2019

Front. Cell. Infect. Microbiol.

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“…In addition, ACA caused also the formation and accumulation of lipid bodies in the parasites. Since lipid droplets are related to organelles that regulate the storage of neutral lipids, composed of triacylglycerols and sterol esters [ 30 ], this observation could imply cellular stress [ 26 , 40 , 44 ]. Concordantly, treatment with ACA significantly increased the levels of neutral lipids, suggesting the occurrence of cell disorders followed by parasite death.…”

Section: Discussionmentioning

confidence: 99%

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

Costa

Oliveira‐da‐Silva

Reis

et al. 2021

Med Microbiol Immunol

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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.

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“…Lopinavir, an anti-HIV drug in the category of protease inhibitor and is another popular drug that has been reported to have strong positive results in a few trials (66)(67)(68)(69)(70)(71). It is one of the highest ranked drugs in our screening with a binding energy of -9.3 kcal/mol against nsp15.…”

Section: Drugs Under Clinical Trialsmentioning

confidence: 99%

Systemic in Silico Screening in Drug Discovery for Coronavirus Disease (COVID-19) with an Online Interactive Web Server

Xu¹,

Ke²,

Liu³

et al. 2020

Preprint

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<p>The emergence of the new coronavirus (nCoV-19) has brought global impact on human health, whilst the interaction between the virus and the host is the foundation of the disease. The viral genome codes a cluster of proteins, each with a unique function in the event of host invasion or viral development. Under current adverse situation, we employ virtual screening tools in searching for drugs and nature products which have been already deposited in the DrugBank in attempt to accelerate the drug discovery process. This study provides an initial evaluation of current drug candidates from various reports using our systemic in silico drug screening based on structures of viral proteins and human ACE2 receptor. Besides, we built an interactive online platform (<a href="https://shennongproject.com:11443/#/home">https://shennongproject.com:11443/#/home</a>) for browsing these results with the visual display of small molecule docked on its potential target protein, without installing any specialized structural software. With continuous maintenance and incorporation of data from laboratory works, it may serve not only as the assessment tool for the new drug discovery but also an educational website to meet general interest from the public.</p>

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Lopinavir, an HIV-1 peptidase inhibitor, induces alteration on the lipid metabolism ofLeishmania amazonensispromastigotes

Cited by 12 publications

References 56 publications

Miltefosine-Lopinavir Combination Therapy Against Leishmania infantum Infection: In vitro and in vivo Approaches

Miltefosine-Lopinavir Combination Therapy Against Leishmania infantum Infection: In vitro and in vivo Approaches

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

Systemic in Silico Screening in Drug Discovery for Coronavirus Disease (COVID-19) with an Online Interactive Web Server

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