GS-8374, a prototype phosphonate-containing inhibitor of HIV-1 protease, effectively inhibits protease mutants with amino acid insertions
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
24371077
PubMed Central
PMC3957959
DOI
10.1128/jvi.02688-13
PII: JVI.02688-13
Knihovny.cz E-resources
- MeSH
- HIV Infections drug therapy virology MeSH
- HIV-1 chemistry drug effects enzymology genetics MeSH
- HIV Protease chemistry genetics metabolism MeSH
- HIV Protease Inhibitors chemistry pharmacology MeSH
- Mutagenesis, Insertional * MeSH
- Crystallography, X-Ray MeSH
- Humans MeSH
- Models, Molecular MeSH
- Organophosphonates analysis MeSH
- Amino Acid Sequence MeSH
- Binding Sites MeSH
- Drug Resistance, Viral MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- HIV Protease MeSH
- HIV Protease Inhibitors MeSH
- Organophosphonates MeSH
- p16 protease, Human immunodeficiency virus 1 MeSH Browser
Insertions in the protease (PR) region of human immunodeficiency virus (HIV) represent an interesting mechanism of antiviral resistance against HIV PR inhibitors (PIs). Here, we demonstrate the improved ability of a phosphonate-containing experimental HIV PI, GS-8374, relative to that of other PIs, to effectively inhibit patient-derived recombinant HIV strains bearing PR insertions and numerous other mutations. We correlate enzyme inhibition with the catalytic activities of corresponding recombinant PRs in vitro and provide a biochemical and structural analysis of the PR-inhibitor complex.
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Kohl NE, Emini EA, Schleif WA, Davis LJ, Heimbach JC, Dixon RAF, Scolnick EM, Sigal IS. 1988. Active human immunodeficiency virus protease is required for viral infectivity. Proc. Natl. Acad. Sci. U. S. A. 85:4686–4690. 10.1073/pnas.85.13.4686 PubMed DOI PMC
Wlodawer A, Vondrasek J. 1998. Inhibitors of HIV-1 protease: a major success of structure-assisted drug design. Annu. Rev. Biophys. Biomol. Struct. 27:249–284. 10.1146/annurev.biophys.27.1.249 PubMed DOI
Pokorna J, Machala L, Rezacova P, Konvalinka J. 2009. Current and novel inhibitors of HIV protease. Viruses 1:1209–1239. 10.3390/v1031209 PubMed DOI PMC
Menendez-Arias L. 2013. Molecular basis of human immunodeficiency virus type 1 drug resistance: overview and recent developments. Antiviral Res. 98:93–120. 10.1016/j.antiviral.2013.01.007 PubMed DOI
Fun A, Wensing AMJ, Verheyen J, Nijhuis M. 2012. Human immunodeficiency virus gag and protease: partners in resistance. Retrovirology 9:63. 10.1186/1742-4690-9-63 PubMed DOI PMC
Amiel C, Charpentier C, Desire N, Bonnard P, Lebrette M-G, Weiss L, Pialoux G, Schneider V. 2011. Long-term follow-up of 11 protease inhibitor (PI)-naive and PI-treated HIV-infected patients harbouring virus with insertions in the HIV-1 protease gene. HIV Med. 12:138–144. 10.1111/j.1468-1293.2010.00862.x PubMed DOI
Kozisek M, Saskova KG, Rezacova P, Brynda J, van Maarseveen NM, de Jong D, Boucher CA, Kagan RM, Nijhuis M, Konvalinka J. 2008. Ninety-nine is not enough: molecular characterization of inhibitor resistant human immunodeficiency virus type 1 protease mutants with insertions in the flap region. J. Virol. 82:5869–5878. 10.1128/JVI.02325-07 PubMed DOI PMC
Chen JHK, Wong KH, Chan KC, Lam HY, Yuen KY, Cheng VCC, Yam WC. 2008. Molecular epidemiology and divergence of HIV type 1 protease codon 35 inserted strains among treatment-naive patients in Hong Kong 2008. AIDS Res. Hum. Retroviruses 24:537–542. 10.1089/aid.2007.0231 PubMed DOI
Paolucci S, Baldanti F, Dossena L, Gerna G. 2006. Amino acid insertions at position 35 of HIV-1 protease interfere with virus replication without modifying antiviral drug susceptibility. Antiviral Res. 69:181–185. 10.1016/j.antiviral.2005.12.005 PubMed DOI
Pereira-Vaz J, Duque V, Trindade L, Saraiva-Da-Cunh J, Melico-Silvestre A. 2009. Detection of the protease codon 35 amino acid insertion in sequences from treatment-naive HIV-1 subtype C infected individuals in the Central Region of Portugal. J. Clin. Virol. 46:169–172. 10.1016/j.jcv.2009.06.019 PubMed DOI
Grotto RMT, Corvino SM, Munhoz LDR, Ghedini CG, Pardini MIDC. 2011. A first case of protease codon 35 amino acid insertion in a HIV-1 subtype B sequence detected in the Bauru Region, State of Sao Paulo, Brazil: case report. Rev. Soc. Bras. Med. Trop. 44:392–394. 10.1590/S0037-868220110003000027 PubMed DOI
Callebaut C, Stray K, Tsai L, Williams M, Yang ZY, Cannizzaro C, Leavitt SA, Liu XH, Wang K, Murray BP, Mulato A, Hatada M, Priskich T, Parkin N, Swaminathan S, Lee W, He GX, Xu LH, Cihlar T. 2011. In vitro characterization of GS-8374, a novel phosphonate-containing inhibitor of HIV-1 protease with a favorable resistance profile. Antimicrob. Agents Chemother. 55:1366–1376. 10.1128/AAC.01183-10 PubMed DOI PMC
Ghosh AK, Chapsal BD, Weber IT, Mitsuya H. 2008. Design of HIV protease inhibitors targeting protein backbone: an effective strategy for combating drug resistance. Acc. Chem. Res. 41:78–86. 10.1021/ar7001232 PubMed DOI
Ghosh AK, Pretzer E, Cho H, Hussain KA, Duzgunes N. 2002. Antiviral activity of UIC-PI, a novel inhibitor of the human immunodeficiency virus type 1 protease. Antiviral Res. 54:29–36. 10.1016/S0166-3542(01)00209-1 PubMed DOI
Kozisek M, Bray J, Rezacova P, Saskova K, Brynda J, Pokorna J, Mammano F, Rulisek L, Konvalinka J. 2007. Molecular analysis of the HIV-1 resistance development: enzymatic activities, crystal structures, and thermodynamics of nelfinavir-resistant HIV protease mutants. J. Mol. Biol. 374:1005–1016. 10.1016/j.jmb.2007.09.083 PubMed DOI
Weber J, Mesters JR, Lepsik M, Prejdova J, Svec M, Sponarova J, Mlcochova P, Skalicka K, Strisovsky K, Uhlikova T, Soucek M, Machala L, Stankova M, Vondrasek J, Klimkait T, Kräusslich H-G, Hilgenfeld R, Konvalinka K. 2002. Unusual binding mode of an HIV-1 protease inhibitor explains its potency against multi-drug-resistant virus strains. J. Mol. Biol. 324:739–754. 10.1016/S0022-2836(02)01139-7 PubMed DOI
Hazen R, Harvey R, Ferris R, Craig C, Yates P, Griffin P, Miller J, Kaldor I, Ray J, Samano V, Furfine E, Spaltenstein A, Hale M, Tung R, St Clair M, Hanlon M, Boone L. 2007. In vitro antiviral activity of the novel, tyrosyl-based human immunodeficiency virus (HIV) type 1 protease inhibitor brecanavir (GW640385) in combination with other antiretrovirals and against a panel of protease inhibitor-resistant HIV. Antimicrob. Agents Chemother. 51:3147–3154. 10.1128/AAC.00401-07 PubMed DOI PMC
Cihlar T, He GX, Liu X, Chen JM, Hatada M, Swaminathan S, McDermott MJ, Yang ZY, Mulato AS, Chen X, Leavitt SA, Stray KM, Lee WA. 2006. Suppression of HIV-1 protease inhibitor resistance by phosphonate-mediated solvent anchoring. J. Mol. Biol. 363:635–647. 10.1016/j.jmb.2006.07.073 PubMed DOI
Winters MA, Merigan TC. 2005. Insertions in the human immunodeficiency virus type 1 protease and reverse transcriptase genes: clinical impact and molecular mechanisms. Antimicrob. Agents Chemother. 49:2575–2582. 10.1128/AAC.49.7.2575-2582.2005 PubMed DOI PMC
Boom R, Sol C, Gerrits Y, De Boer M, Wertheim-van Dillen P. 1999. A highly sensitive assay for detection and quantitation of human cytomegalovirus DNA in serum and plasma by PCR and electrochemiluminescence. J. Clin. Microbiol. 37:1489–1497 PubMed PMC
PDB
4M8X, 4M8Y
