Antiviral properties of Ro 31-8959, an inhibitor of human immunodeficiency virus (HIV) proteinase

Craig, Jane; Duncan, I. B. R.; Hockley, David J.; Grief, C.; Roberts, Noel A.; Mills, John

doi:10.1016/0166-3542(91)90045-s

Cited by 173 publications

(89 citation statements)

References 9 publications

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“…The compound Ro31-8959 (16 in Table 4) is a potent inhibitor of proteinase from HIV-1 and HIV-2 [24] and from SIV [25] but was found to be ineffective against wild-type EIAV proteinase. Similarly, it did not inhibit purified proteinases from HTLV-1 [26] and FIV (B. M. D. and D. J. P., unpublished observation) and was unable to impair the replication cycle of a number of other retroviruses [27]. Proteinases from the three susceptible viruses, HIV-1, HIV-2 and SIV, all have a Gly at position 48 ( Fig.…”

Section: Discussionmentioning

confidence: 91%

Expression, Characterisation and Mutagenesis of the Aspartic Proteinase from Equine Infectious Anaemia Virus

Powell

Bur

Wlodawer

et al. 1996

European Journal of Biochemistry

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The gene encoding the proteinase from equine infectious anaemia virus (EIAV) was cloned and expressed in Escherichia coli. The recombinant EIAV proteinase was purified to homogeneity and shown to have the ability to process polyprotein and synthetic peptide substrates of human immunodeficiency virus (HIV) origin with an efficiency that can approach that exhibited by HIV proteinase. EIAV proteinase, however, was not susceptibfe to inhibition by a wide variety of inhibitors of HIV-1 proteinase, including those which have been licenced as anti-AIDS drugs. In this respect, EIAV proteinase behaves like an extreme case of a drug-resistant mutant of HIV-1 proteinase that has arisen under selective drug pressure. Only one potent inhibitor (HBY-793) of HIV-1 proteinase showed comparable efficiency against the EIAV enzyme; the compounds A-77003 and A-76889, which differ only in their stereochemistry and which are otherwise structurally identical to HBY-793 from residues P2 to P2' [nomenclature of Schechter, I.

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Section: Discussionmentioning

confidence: 91%

Expression, Characterisation and Mutagenesis of the Aspartic Proteinase from Equine Infectious Anaemia Virus

Powell

Bur

Wlodawer

et al. 1996

European Journal of Biochemistry

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“…However, the results suggest that the protease inhibitor primarily interfered at a stage after the triggering point for the induction of apoptosis and therefore could not completely prevent apoptosis (Table 1). Of note, the cleavage of gpl60 into its two components gp41 and gpl20 would remain unaffected by the aspartic protease inhibitor utilized in this experiment because a cellular serine protease, unaffected by this inhibitor, is responsible for this enzymatic cleavage (Craig et al, 1991). Therefore, viral budding and the presence of viral glycoproteins at the surface of the infected cells and non-infectious virus budding would remain unaffected.…”

Section: J Corbeil and D D Richmanmentioning

confidence: 99%

“…4aS, 8aS-isoquinoline-3(S)-carboxamide methanesulphonate) (Roche Products) (Craig et al, 1991) and the anti-CD4 antibody Leu3a (Becton-Dickinson) (Attanasio et al, 1991).…”

Section: Hiv-1 Infection and Utili=ation Of Hiv Inhibitors The Infecmentioning

confidence: 99%

Productive infection and subsequent interaction of CD4-gp120 at the cellular membrane is required for HIV-induced apoptosis of CD4+ T cells

Corbeil

Richman

1995

Journal of General Virology

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“…Inhibition of syncytium formation was carried out as described previously (Craig et al, 1991). Briefly, CEM cells in exponential growth were infected with HIV-1 strain GB8 at a multiplicity of infection of 0.005 syncytium-forming units celr".…”

Section: Syncytium Reduction Assaymentioning

confidence: 99%

In vitro Resistance to an Inhibitor of HIV Proteinase (Ro 31-8959) Relative to Inhibitors of Reverse Transcriptase (AZT and TIBO)

Craig

Whittaker

Duncan

et al. 1993

Antivir Chem Chemother

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SummarySerial passage of cell-free human immunodeficiency virus type 1 (HIV-1) strain GB8 on CEM cells was carried out in the presence of increasing concentrations of the HIV proteinase inhibit~r Ro 31-8959 in parallel with representative revers~(tanscriptase (RT) inhibitors (AZT and the TIBO compo'und, R82150).ln all instances, a significant increase in the concentration of compound required to produce a 90% reduction of syncytium formation (ICgo) was found after seven to nine passages of virus. Reduced sensitivity to Ro 31-8959 was confirmed by p24 ELISA. Virus passaged in the presence of RT inhibitors did not show a significant change in either the ability to grow in culture supplemented with step-wise increments of inhibitor concentration or the rate of growth in the presence of compound. In contrast, virus passaged in the presence of Ro 31-8959 required, on average, more than 2.5-times the normal passage time and often did not replicate when increases in inhibitor concentration were applied during the initial passages.The results show that reduced sensitivity to an inhibitor of HIV proteinase, Ro 31-8959, can be generated, but it would seem to arise less readily than that found with either of the RT inhibitors studied. While this study indicates the potential for a reduction in sensitivity to proteinase inhibitors, it does not necessarily reflect the ability of mutant virus either to be selected for or to be propagated in the clinic.

show abstract

Antiviral properties of Ro 31-8959, an inhibitor of human immunodeficiency virus (HIV) proteinase

Cited by 173 publications

References 9 publications

Expression, Characterisation and Mutagenesis of the Aspartic Proteinase from Equine Infectious Anaemia Virus

Expression, Characterisation and Mutagenesis of the Aspartic Proteinase from Equine Infectious Anaemia Virus

Productive infection and subsequent interaction of CD4-gp120 at the cellular membrane is required for HIV-induced apoptosis of CD4+ T cells

In vitro Resistance to an Inhibitor of HIV Proteinase (Ro 31-8959) Relative to Inhibitors of Reverse Transcriptase (AZT and TIBO)

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