Morphological alterations and growth inhibition of Leishmania (L.)amazonensis promastigotes exposed to zidovudine (AZT)

Araújo, Carolina Akiko Sato Cabral; Araújo, Aline A.; Batista, Camilla L.; Oliveira, Milton Adriano Pelli de; Oliveira, Valéria de; Lino, Ruy S.; Vinaud, Marina Clare; Bezerra, José Clecildo Barreto

doi:10.1007/s00436-010-2096-3

Cited by 9 publications

(5 citation statements)

References 17 publications

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“…Moreover, we were able to confirm dTTP and AP 5 dT as potent inhibitors of Lm TK. We showed AZT and 5’-modified dUrd to be readily phosphorylated by LmT K and this compound was shown previously to inhibit Leishmania intracellular amastigote growth and to exhibit potential as an antiprotozoal agent [ 54 ]. However, the lack of major structural differences in the active site of Lm TK compared to the hTK1, further validated by the similarity in their kinetic parameters for dUrd, 5F-2’dU and AZT ( Table 2 ), might render the design of Lm TK-specific ligands challenging.…”

Section: Resultsmentioning

confidence: 99%

Structural and Kinetic Characterization of Thymidine Kinase from Leishmania major

et al. 2015

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Leishmania spp. is a protozoan parasite and the causative agent of leishmaniasis. Thymidine kinase (TK) catalyses the transfer of the γ-phosphate of ATP to 2’-deoxythymidine (dThd) forming thymidine monophosphate (dTMP). L. major Type II TK (LmTK) has been previously shown to be important for infectivity of the parasite and therefore has potential as a drug target for anti-leishmanial therapy. In this study, we determined the enzymatic properties and the 3D structures of holo forms of the enzyme. LmTK efficiently phosphorylates dThd and dUrd and has high structural homology to TKs from other species. However, it significantly differs in its kinetic properties from Trypanosoma brucei TK since purines are not substrates of the enzyme and dNTPs such as dUTP inhibit LmTK. The enzyme had Km and kcat values for dThd of 1.1 μM and 2.62 s-1 and exhibits cooperative binding for ATP. Additionally, we show that the anti-retroviral prodrug zidovudine (3-azido-3-deoxythymidine, AZT) and 5’-modified dUrd can be readily phosphorylated by LmTK. The production of recombinant enzyme at a level suitable for structural studies was achieved by the construction of C-terminal truncated versions of the enzyme and the use of a baculoviral expression system. The structures of the catalytic core of LmTK in complex with dThd, the negative feedback regulator dTTP and the bi-substrate analogue AP5dT, were determined to 2.74, 3.00 and 2.40 Å, respectively, and provide the structural basis for exclusion of purines and dNTP inhibition. The results will aid the process of rational drug design with LmTK as a potential target for anti-leishmanial drugs.

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Section: Resultsmentioning

confidence: 99%

Structural and Kinetic Characterization of Thymidine Kinase from Leishmania major

et al. 2015

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“…Some studies have reported antiprotozoal activity of HAART in Leishmania (Araújo et al, 2011;Kumar et al, 2008;Santos et al, 2009;Savoia, Allice, Tovo, 2005;Valdivieso et al, 2010). AZT significantly decreased the number of Leishmania parasites due to its toxicity and caused morphometric alterations such as an increase in width of the body, cytoplasmic granulation and vacuolization (Araújo et al, 2011).…”

Section: Antiretroviral Drugs and Protozoa Agentsmentioning

confidence: 99%

“…AZT significantly decreased the number of Leishmania parasites due to its toxicity and caused morphometric alterations such as an increase in width of the body, cytoplasmic granulation and vacuolization (Araújo et al, 2011). PIs such as ritonavir, indinavir and saquinavir have reduced the number of Leishmania promastigotes in vitro (Savoia, Allice, Tovo, 2005).…”

Section: Antiretroviral Drugs and Protozoa Agentsmentioning

confidence: 99%

Activity of antiretroviral drugs in human infections by opportunistic agents

Demarchi

Cardozo

Aristides

et al. 2012

Braz. J. Pharm. Sci.

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Highly active antiretroviral therapy (HAART) is used in patients infected with HIV. This treatment has been shown to significantly decrease opportunist infections such as those caused by viruses, fungi and particularly, protozoa. The use of HAART in HIV-positive persons is associated with immune reconstitution as well as decreased prevalence of oral candidiasis and candidal carriage. Antiretroviral therapy benefits patients who are co-infected by the human immunodeficiency virus (HIV), human herpes virus 8 (HHV-8), Epstein-Barr virus, hepatitis B virus (HBV), parvovirus B19 and cytomegalovirus (CMV). HAART has also led to a significant reduction in the incidence, and the modification of characteristics, of bacteremia by etiological agents such as Staphylococcus aureus, coagulase negative staphylococcus, non-typhoid species of Salmonella, Streptococcus pneumoniae, Pseudomonas aeruginosa, and Mycobacterium tuberculosis. HAART can modify the natural history of cryptosporidiosis and microsporidiosis, and restore mucosal immunity, leading to the eradication of Cryptosporidium parvum. A similar restoration of immune response occurs in infections by Toxoplasma gondii. The decline in the incidence of visceral leishmaniasis/HIV co-infection can be observed after the introduction of protease inhibitor therapy. Current findings are highly relevant for clinical medicine and may serve to reduce the number of prescribed drugs thereby improving the quality of life of patients with opportunistic diseases.
A terapia HAART (terapia antirretroviral altamente ativa) é usada em pacientes infectados pelo vírus da imunodeficiência humana (HIV) e demonstrou diminuição significativa de infecções oportunistas, tais como as causadas por vírus, fungos, protozoários e bactérias. O uso da HAART está associado com a reconstituição imunológica e diminuição na prevalência de candidíase oral. A terapia antirretroviral beneficia pacientes co-infectados pelo HIV, vírus herpes humano 8 (HHV-8), vírus Epstein-Barr (EBV), vírus da hepatite B (HBV), parvovírus B19 e citomegalovírus (CMV). A HAART também apresentou redução significativa da incidência e modificou as características da bacteremia por agentes etiológicos, tais como Staphylococcus aureus, espécies não-tifóides de Salmonella, Streptococcus pneumoniae, Pseudomonas aeruginosa, Mycobacterium tuberculosis. A HAART é capaz de modificar significativamente a história natural da criptosporidiose e microsporidiose. HAART pode efetivamente restaurar a imunidade da mucosa, levando à erradicação de Cryptosporidium parvum. Semelhante restauração da resposta imune ocorre em infecções por Toxoplasma gondii. O declínio na incidência de co-infecção leishmaniose visceral/HIV pode ser observada após a introdução da terapia com inibidores da protease. Os resultados atuais são altamente relevantes para a medicina clínica e podem proporcionar diminuição no número de prescrições medicamentosas e, consequentemente, melhor qualidade de vida para pacientes com doenças oportunistas

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“…Although there are limited in vitro data suggesting that HIV-1 protease inhibitors and possibly some other antiretroviral drugs might directly exert inhibitory effects on Leishmania , there is insufficient evidence for their clinical use against VL, and standard ART regimens are currently recommended in VL–HIV coinfection ( 5 ). In low income countries, this is provided by standardized first- and second-line regimens in a public health approach ( 20 , 21 ).…”

Section: Introductionmentioning

confidence: 99%

Immunomodulatory Therapy of Visceral Leishmaniasis in Human Immunodeficiency Virus-Coinfected Patients

et al. 2018

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Patients with visceral leishmaniasis (VL)–human immunodeficiency virus (HIV) coinfection experience increased drug toxicity and treatment failure rates compared to VL patients, with more frequent VL relapse and death. In the era of VL elimination strategies, HIV coinfection is progressively becoming a key challenge, because HIV-coinfected patients respond poorly to conventional VL treatment and play an important role in parasite transmission. With limited chemotherapeutic options and a paucity of novel anti-parasitic drugs, new interventions that target host immunity may offer an effective alternative. In this review, we first summarize current views on how VL immunopathology is significantly affected by HIV coinfection. We then review current clinical and promising preclinical immunomodulatory interventions in the field of VL and discuss how these may operate in the context of a concurrent HIV infection. Caveats are formulated as these interventions may unpredictably impact the delicate balance between boosting of beneficial VL-specific responses and deleterious immune activation/hyperinflammation, activation of latent provirus or increased HIV-susceptibility of target cells. Evidence is lacking to prioritize a target molecule and a more detailed account of the immunological status induced by the coinfection as well as surrogate markers of cure and protection are still required. We do, however, argue that virologically suppressed VL patients with a recovered immune system, in whom effective antiretroviral therapy alone is not able to restore protective immunity, can be considered a relevant target group for an immunomodulatory intervention. Finally, we provide perspectives on the translation of novel theories on synergistic immune cell cross-talk into an effective treatment strategy for VL–HIV-coinfected patients.

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Morphological alterations and growth inhibition of Leishmania (L.)amazonensis promastigotes exposed to zidovudine (AZT)

Cited by 9 publications

References 17 publications

Structural and Kinetic Characterization of Thymidine Kinase from Leishmania major

Structural and Kinetic Characterization of Thymidine Kinase from Leishmania major

Activity of antiretroviral drugs in human infections by opportunistic agents

Immunomodulatory Therapy of Visceral Leishmaniasis in Human Immunodeficiency Virus-Coinfected Patients

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