Martin Hradílek

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Secreted aspartic proteinases (Sap) play a role in the virulence of pathogenic Candida spp. Candida parapsilosis possesses three genes encoding these enzymes: SAPP1, SAPP2, and SAPP3. We analyzed the expression of the SAPP1 and SAPP2 genes and the production of Sapp1p and Sapp2p proteinases in the presence of different nitrogen sources. While the SAPP2(More)
The human fungal pathogen Candida parapsilosis possesses at least three genes encoding secreted aspartic proteinases. Whereas the Sapp1p isoenzyme has already been biochemically characterized, the SAPP2 and SAPP3 gene products have not. The Sapp2p precursor, pro-Sapp2p, was therefore expressed in Escherichia coli and purified. Autoactivation of pro-Sapp2p(More)
Secreted aspartic proteases (Saps) of pathogenic Candida spp. represent a specific target for antifungal drug development. We synthesized a series of peptidomimetic inhibitors with different isosteric groups and modifications at individual positions and tested them with purified Saps from C. albicans (Sap2p), C. tropicalis (Sapt1p), and C. parapsilosis(More)
Human immunodeficiency virus (HIV) proteinase (PR) represents an important target for antiviral chemotherapy. We present an analysis of inhibitory activities of a series of pseudopeptide inhibitors of HIV-1 PR. All inhibitors were N-protected tetrapeptides with the scissile bond replaced by a nonhydrolysable hydroxyethylene or hydroxyethylamine isostere. To(More)
Depending on the excess of ligand used for complex formation, the HIV-1 protease complexed with a novel phenylnorstatine inhibitor forms crystals of either hexagonal (P6(1)) or orthorhombic (P2(1)2(1)2(1)) symmetry. The orthorhombic form shows an unusual complexity of crystal packing: in addition to one inhibitor molecule that is bound to the enzyme active(More)
BACKGROUND Blood flukes of the genus Schistosoma cause schistosomiasis, a parasitic disease that infects over 240 million people worldwide, and for which there is a need to identify new targets for chemotherapeutic interventions. Our research is focused on Schistosoma mansoni prolyl oligopeptidase (SmPOP) from the serine peptidase family S9, which has not(More)
Two new X-ray structures of an HIV-1 protease mutant (A71V, V82T, I84V) in complex with inhibitors SE and SQ, pseudotetrapeptide inhibitors with an acyclic S-hydroxyethylamine isostere, were determined. Comparison of eight structures exploring the binding of four similar inhibitors--SE, SQ (S-hydroxyethylamine isostere), OE (ethyleneamine), and QF34(More)
Proteases that digest the blood-meal of the parasitic fluke Schistosoma are potential targets for therapy of schistosomiasis, a disease of chronic morbidity in humans. We generated a three-dimensional model of the cathepsin D target protease of Schistosoma japonicum (SjCD) utilizing the crystal structure of human cathepsin D (huCD) in complex with pepstatin(More)
Crystallization conditions for an HIV-1 protease-inhibitor complex were optimized to produce crystals suitable for X-ray diffraction experiments. The X-ray structure of the HIV-1 protease complex was solved and refined at 3.1 A resolution. In contrast to Saquinavir, the mimetic hydroxy group of the inhibitor Boc-Phe-Psi[(S)-CH(OH)CH(2)NH]-Phe-Glu-Phe-NH(2)(More)
In order to identify inhibitors of various drug-resistant forms of the human immunodeficiency virus protease (HIV PR), we have designed and synthesized pseudopeptide libraries with a general structure Z-mimetic-Aa1-Aa2-NH2. Five different chemistries for peptide bond replacement have been employed and the resulting five individual sublibraries tested with(More)