title: Nelfinavir is effective in inhibiting the multiplication and aspartic peptidase activity of Leishmania species, including strains obtained from HIV-positive patients.
abstract: OBJECTIVE
  There is a general lack of effective and non-toxic chemotherapeutic agents for leishmaniasis and there is as yet no study about the effect of HIV peptidase inhibitors (HIV PIs) on Leishmania/HIV-coinfected patients. In the present work, we performed a comparative analysis of the spectrum of action of HIV PIs on different Leishmania spp., including strains obtained from HIV-positive patients receiving or not receiving antiretroviral treatment.
  
  
  METHODS
  The effects of nelfinavir and saquinavir on Leishmania proliferation were assessed by means of a colorimetric assay (MTT). Subsequently, the effect of nelfinavir on aspartic peptidase activity from Leishmania spp. was assessed by following the degradation of the fluorogenic substrate MCA-G-K-P-I-L-F-F-R-L-K-DNP-Arg-NH(2).
  
  
  RESULTS
  Nelfinavir was capable of significantly reducing the multiplication of many Leishmania reference strains and isolates obtained from HIV-positive patients receiving or not receiving antiretroviral treatment. Leishmania major growth was inhibited by ≈ 50%, while all other flagellates were strongly inhibited (at least 94%), except for a Leishmania chagasi strain obtained from an HIV-positive patient under treatment with highly active antiretroviral therapy (HAART). Culture of this isolate in the presence of nelfinavir induced a considerable reduction in the aspartic peptidase activity. In addition, nelfinavir was also capable of inhibiting the aspartic peptidase activity of all Leishmania strains tested.
  
  
  CONCLUSIONS
  The present data contribute to the study of the effect of HIV PIs on Leishmania infection and add new insights into the possibility of exploiting aspartic peptidases as promising targets in order to generate novel medications to treat leishmaniasis.
authors.affiliation: Laboratório de Biologia Molecular e Doenças Endêmicas,  Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro,  Brazil.
authors.forename: Lívia O
authors.initials: LO
authors.lastname: Santos
authors.forename: Bianca S
authors.initials: BS
authors.lastname: Vitório
authors.forename: Marta H
authors.initials: MH
authors.lastname: Branquinha
authors.forename: Conceição M
authors.initials: CM
authors.lastname: Pedroso e Silva
authors.forename: André L S
authors.initials: AL
authors.lastname: Santos
authors.forename: Claudia M
authors.initials: CM
authors.lastname: d'Avila-Levy
mesh_terms: D000981:Antiprotozoal Agents / Q000494:pharmacology*; D057055:Aspartic Acid Proteases / Q000037:antagonists & inhibitors*; D003124:Colorimetry; D005470:Fluorometry; D015658:HIV Infections / Q000150:complications; D006801:Humans; D007891:Leishmania / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development / Q000302:isolation & purification; D007896:Leishmaniasis / Q000469:parasitology*; D050296:Microbial Viability; D019888:Nelfinavir / Q000494:pharmacology*; D009842:Oligopeptides / Q000378:metabolism; D019258:Saquinavir / Q000494:pharmacology; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism
chemical_list: D000981:Antiprotozoal Agents; C495485:Mca-Lys-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2; D009842:Oligopeptides; D013778:Tetrazolium Salts; D013844:Thiazoles; D057055:Aspartic Acid Proteases; C022616:thiazolyl blue; D019888:Nelfinavir; D019258:Saquinavir