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The crystal structure of protease Sapp1p from Candida parapsilosis in complex with the HIV protease inhibitor ritonavir.

Dostál J, Brynda J, Hrušková-Heidingsfeldová O, Pachl P, Pichová I, Rezáčová P
J Enzyme Inhib Med Chem 27 160-5 (2012)
Cited: 6 times
EuropePMC logo PMID: 22146051

Abstract

Secreted aspartic proteases (Saps) are extracellular proteolytic enzymes that enhance the virulence of Candida pathogens. These enzymes therefore represent possible targets for therapeutic drug design. Saps are inhibited by nanomolar concentrations of the classical inhibitor of aspartic proteases pepstatin A and also by the inhibitors of the HIV protease, but with the K(i) of micromolar values or higher. To contribute to the discussion regarding whether HIV protease inhibitors can act against opportunistic mycoses by the inhibition of Saps, we determined the structure of Sapp1p from Candida parapsilosis in complex with ritonavir (RTV), a clinically used inhibitor of the HIV protease. The crystal structure refined at resolution 2.4 Å proved binding of RTV into the active site of Sapp1p and provided the structural information necessary to evaluate the stability and specificity of the protein-inhibitor interaction.

Reviews citing this publication (1)

  1. Extracellular proteinases of Candida species pathogenic yeasts. Rapala-Kozik M, Bochenska O, Zajac D, Karkowska-Kuleta J, Gogol M, Zawrotniak M, Kozik A. Mol Oral Microbiol 33 113-124 (2018)

Articles citing this publication (5)

  1. Atomic resolution crystal structure of Sapp2p, a secreted aspartic protease from Candida parapsilosis. Dostál J, Pecina A, Hrušková-Heidingsfeldová O, Marečková L, Pichová I, Řezáčová P, Lepšík M, Brynda J. Acta Crystallogr. D Biol. Crystallogr. 71 2494-2504 (2015)
  2. Insight into the structural similarity between HIV protease and secreted aspartic protease-2 and binding mode analysis of HIV-Candida albicans inhibitors. Calugi C, Guarna A, Trabocchi A. J Enzyme Inhib Med Chem 28 936-943 (2013)
  3. Repositioning Lopinavir, an HIV Protease Inhibitor, as a Promising Antifungal Drug: Lessons Learned from Candida albicans-In Silico, In Vitro and In Vivo Approaches. Santos ALS, Braga-Silva LA, Gonçalves DS, Ramos LS, Oliveira SSC, Souza LOP, Oliveira VS, Lins RD, Pinto MR, Muñoz JE, Taborda CP, Branquinha MH. J Fungi (Basel) 7 424 (2021)
  4. Aspartic peptidase of Phialophora verrucosa as target of HIV peptidase inhibitors: blockage of its enzymatic activity and interference with fungal growth and macrophage interaction. Granato MQ, Sousa IS, Rosa TLSA, Gonçalves DS, Seabra SH, Alviano DS, Pessolani MCV, Santos ALS, Kneipp LF. J Enzyme Inhib Med Chem 35 629-638 (2020)
  5. Structural determinants for subnanomolar inhibition of the secreted aspartic protease Sapp1p from Candida parapsilosis. Dostál J, Brynda J, Vaňková L, Zia SR, Pichová I, Heidingsfeld O, Lepšík M. J Enzyme Inhib Med Chem 36 914-921 (2021)


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