Locking the two ends of tetrapeptidic HTLV-I protease inhibitors inside the enzyme

Zhang, Meihui; Nguyen, Jeffrey‐Tri; Kumada, Henri-Obadja; Kimura, Tooru; Cheng, Maosheng; Hayashi, Yoshio; Kiso, Yoshiaki

doi:10.1016/j.bmc.2008.05.052

Cited by 16 publications

(11 citation statements)

References 23 publications

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“…The inhibitors used in this study for cocrystallization with HTLV-1 PR included the statine-based inhibitor studied previously13,19, as well as a number of inhibitors that were specifically designed to inhibit this enzyme18,20,21. Although some of the inhibitor complexes did not crystallize, others did, yielding several different crystal forms (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…By comparison, a number of subpicomolar inhibitors of HIV-1 PR have been developed using the principles of rational drug design17. Most recently, inhibition properties of a series of HTLV-1 inhibitors that contain allophenylnorstatine [(2 S ,3 S )-3-amino-2-hydroxy-4-phenylbutyric acid, Apns] isostere derived from a scissile amino acid sequence Leu-Pro found in an efficiently processed enzyme substrate have been characterized in detail and a qualitative structure-activity relationship (QSAR) equation has been derived18. However, that study lacked direct structural confirmation of the mode of binding of that series of inhibitors to the target enzyme.…”

Section: Introductionmentioning

confidence: 99%

“…For that purpose, we expressed the previously used L40I mutant of HTLV-1 PR in a different bacterial strain, improved the purification procedures, and searched for new crystallization conditions. Second, in order to provide structural underpinnings to the rational synthesis of the inhibitors of HTLV-1 PR and to explain the QSAR results18, we cocrystallized the enzyme with a number of inhibitors that were previously characterized and analyzed in detail the structures of several such complexes.…”

Section: Introductionmentioning

confidence: 99%

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Crystal Structures of Inhibitor Complexes of Human T-Cell Leukemia Virus (HTLV-1) Protease

Satoh

Nguyen

et al. 2010

Journal of Molecular Biology

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Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus associated with several serious diseases, such as adult T-cell leukemia and tropical spastic paraparesis/myelopathy. For a number of years, the protease (PR) encoded by HTLV-1 has been a target for designing antiviral drugs, but that effort was hampered by limited available structural information. We report here a high resolution crystal structure of HTLV-1 PR complexed with a statine-containing inhibitor, a significant improvement over the previously available moderate resolution structure. We also report crystal structures of the complexes of HTLV-1 PR with five different inhibitors that are more compact and more potent. A detailed structure-activity relationship study was performed to interpret in detail the influence of the polar and hydrophobic interactions between the inhibitors and the protease.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Crystal Structures of Inhibitor Complexes of Human T-Cell Leukemia Virus (HTLV-1) Protease

Satoh

Nguyen

et al. 2010

Journal of Molecular Biology

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“…It has also been shown that inhibitors belonging to this series exhibit good bioavailability and low toxicity (Kiriyama et al, 1996). Further optimization of the KNI inhibitors, supported by extensive structural and biochemical studies, resulted in the synthesis of many new compounds shown to be potent inhibitors of retroviral enzymes, such as HIV-1 and HTLV-1 PRs (Abdel-Rahman et al, 2004; Kimura et al, 2007; Maegawa et al, 2004; Nguyen et al, 2008b; Zhang et al, 2008a; Zhang et al, 2008b). Subsequent experiments have shown that selected KNI inhibitors are also effective against proteases expressed in Plasmodium parasites (Nezami et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Crystal structures of the free and inhibited forms of plasmepsin I (PMI) from Plasmodium falciparum

Bhaumik

Horimoto

Xiao

et al. 2011

Journal of Structural Biology

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Plasmepsin I (PMI) is one of the four vacuolar pepsin-like proteases responsible for hemoglobin degradation by the malarial parasite Plasmodium falciparum, and the only one with no crystal structure reported to date. Due to substantial functional redundancy of these enzymes, lack of inhibition of even a single plasmepsin can defeat efforts in creating effective antiparasitic agents. We have now solved crystal structures of the recombinant PMI as apoenzyme and in complex with the potent peptidic inhibitor, KNI-10006, at the resolution of 2.4 and 3.1 Å, respectively. The apoenzyme crystallized in the orthorhombic space group P212121 with two molecules in the asymmetric unit and the structure has been refined to the final R-factor of 20.7%. The KNI-10006 bound enzyme crystallized in the tetragonal space group P43 with four molecules in the asymmetric unit and the structure has been refined to the final R-factor of 21.1%. In the PMI-KNI-10006 complex, the inhibitors were bound identically to all four enzyme molecules, with the opposite directionality of the main chain of KNI-10006 relative to the direction of the enzyme substrates. Such a mode of binding of inhibitors containing an allophenylnorstatine-dimethylthioproline insert in the P1-P1’ positions, previously reported in a complex with PMIV, demonstrates the importance of satisfying the requirements for the proper positioning of the functional groups in the mechanism-based inhibitors towards the catalytic machinery of aspartic proteases, as opposed to binding driven solely by the specificity of the individual enzymes. A comparison of the structure of the PMI-KNI-10006 complex with the structures of other vacuolar plasmepsins identified the important differences between them and may help in the design of specific inhibitors targeting the individual enzymes.

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“…Computer-assisted docking experiments suggested that, in the symmetrical homodimeric HTLV-I protease, the P 1 0 and P 2 0 -cap moiety resided in the respective mirror pocket of the S 1 and S 2 where the corresponding P 1 and P 2 sidechains fit [193]. In their present research, Kiso et al are exploring the P 2 -cap moiety and other P 1 0 -capping groups to maximize inhibitory activity against HTLV-I protease.…”

Section: Htlv-i Inhibitorsmentioning

confidence: 99%

Medicinal Chemistry of α‐Hydroxy‐β‐Amino Acids

Ziora

Skwarczynski

Kiso

2011

Amino Acids, Peptides and Proteins in Organic Chemistry

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Locking the two ends of tetrapeptidic HTLV-I protease inhibitors inside the enzyme

Cited by 16 publications

References 23 publications

Crystal Structures of Inhibitor Complexes of Human T-Cell Leukemia Virus (HTLV-1) Protease

Crystal Structures of Inhibitor Complexes of Human T-Cell Leukemia Virus (HTLV-1) Protease

Crystal structures of the free and inhibited forms of plasmepsin I (PMI) from Plasmodium falciparum

Medicinal Chemistry of α‐Hydroxy‐β‐Amino Acids

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