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Methodology for screening of HIV inhibitors applicable for in silico designed molecules and empirical testing of traditional medicinal materials

Identifikátory výsledku

  • Kód výsledku v IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F17%3A00506507" target="_blank" >RIV/61388963:_____/17:00506507 - isvavai.cz</a>

  • Výsledek na webu

  • DOI - Digital Object Identifier

Alternativní jazyky

  • Jazyk výsledku

    angličtina

  • Název v původním jazyce

    Methodology for screening of HIV inhibitors applicable for in silico designed molecules and empirical testing of traditional medicinal materials

  • Popis výsledku v původním jazyce

    Nature provides immense variety of biologically active compounds. The beneficial effects of biological materials for humans are well recognized in traditional medicine. However, most of them are still poorly characterized despite immense effort of numerous laboratories. This is in some extent caused also by a quest to identify single compound rather than focusing on synergistic effect of more compounds present in the material either of plant or animal origin. A need for new inhibitors preferentially of natural origin is well justified also for viruses. This is especially true for those viruses that copy genomic material with a low fidelity. This results in continuous emergence of high numbers of drug-resistant viral mutants including those of HIV. In the search for compounds potentially inhibiting HIV, we have recently developed a fluorescent high-throughput assay for screening the inhibitors of assembly of the virus (named FAITH-Fast Assembly Inhibitor Test for HIV) Hadravova et al. (2015). The method was validated using previously reported assembly inhibitors and was shown to be very sensitive and reliable as it provides minimum of false results, as confirmed by electron microscopy. We summarize here the principle and basic protocol of FAITH and we present its application for screening of inhibitors acting in two possible modes. Both of them are essential for complete retrovirus life cycle and thus their inhibition might block virus infectivity, by inhibiting either the assembly of immature particle or disassembly of mature virus core. Based on recently published detailed HIV-1 structure, we designed in silico several compounds presumptively binding to selected interaction interfaces within hexagonal lattice of virus particle. Interestingly, some of the compounds accelerated the assembly, instead of blocking it. This suggests that these compounds bind with a high affinity without preventing the particle formation and thus might block the disassembly of the particle rather than its assembly. As the disassembly is another key step in the virus life cycle, we are currently optimizing the method for screening of the compounds inhibiting the disassembly of the virus core. The method is now being adapted also for other viral species. Both the assembly and disassembly screening methods are applicable also for a non-targeted empirical screening of inhibiting activities of compounds present in biological extracts, preferentially those used in traditional medicine against viral infections. Extremely interesting would be extracts with combined inhibitory activity against HIV and microbial pathogens. These would target not only the primary cause of AIDS but also the microorganisms causing opportunistic infections in AIDS patients.

  • Název v anglickém jazyce

    Methodology for screening of HIV inhibitors applicable for in silico designed molecules and empirical testing of traditional medicinal materials

  • Popis výsledku anglicky

    Nature provides immense variety of biologically active compounds. The beneficial effects of biological materials for humans are well recognized in traditional medicine. However, most of them are still poorly characterized despite immense effort of numerous laboratories. This is in some extent caused also by a quest to identify single compound rather than focusing on synergistic effect of more compounds present in the material either of plant or animal origin. A need for new inhibitors preferentially of natural origin is well justified also for viruses. This is especially true for those viruses that copy genomic material with a low fidelity. This results in continuous emergence of high numbers of drug-resistant viral mutants including those of HIV. In the search for compounds potentially inhibiting HIV, we have recently developed a fluorescent high-throughput assay for screening the inhibitors of assembly of the virus (named FAITH-Fast Assembly Inhibitor Test for HIV) Hadravova et al. (2015). The method was validated using previously reported assembly inhibitors and was shown to be very sensitive and reliable as it provides minimum of false results, as confirmed by electron microscopy. We summarize here the principle and basic protocol of FAITH and we present its application for screening of inhibitors acting in two possible modes. Both of them are essential for complete retrovirus life cycle and thus their inhibition might block virus infectivity, by inhibiting either the assembly of immature particle or disassembly of mature virus core. Based on recently published detailed HIV-1 structure, we designed in silico several compounds presumptively binding to selected interaction interfaces within hexagonal lattice of virus particle. Interestingly, some of the compounds accelerated the assembly, instead of blocking it. This suggests that these compounds bind with a high affinity without preventing the particle formation and thus might block the disassembly of the particle rather than its assembly. As the disassembly is another key step in the virus life cycle, we are currently optimizing the method for screening of the compounds inhibiting the disassembly of the virus core. The method is now being adapted also for other viral species. Both the assembly and disassembly screening methods are applicable also for a non-targeted empirical screening of inhibiting activities of compounds present in biological extracts, preferentially those used in traditional medicine against viral infections. Extremely interesting would be extracts with combined inhibitory activity against HIV and microbial pathogens. These would target not only the primary cause of AIDS but also the microorganisms causing opportunistic infections in AIDS patients.

Klasifikace

  • Druh

    D - Stať ve sborníku

  • CEP obor

  • OECD FORD obor

    10608 - Biochemistry and molecular biology

Návaznosti výsledku

  • Projekt

    Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

  • Návaznosti

    P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Ostatní

  • Rok uplatnění

    2017

  • Kód důvěrnosti údajů

    S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Údaje specifické pro druh výsledku

  • Název statě ve sborníku

    Environmental Technology and Innovations

  • ISBN

    978-1-138-02996-5

  • ISSN

  • e-ISSN

  • Počet stran výsledku

    7

  • Strana od-do

    21-27

  • Název nakladatele

    CRC Press

  • Místo vydání

    Leiden

  • Místo konání akce

    Ho Chi Minh City

  • Datum konání akce

    23. 11. 2016

  • Typ akce podle státní příslušnosti

    WRD - Celosvětová akce

  • Kód UT WoS článku

    000460265400005