Antiviral properties of aminodiol inhibitors against human immunodeficiency virus and protease

Bechtold, Clifford; Patick, Amy K.; Alam, Masud; Greytok, Jill A.; Tino, Joseph A.; Chen, P; Gordon, Eric M.; Ahmad, Saleem; Barrish, Joel C.; Zahler, Robert

doi:10.1128/aac.39.2.374

Cited by 12 publications

(14 citation statements)

References 39 publications

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“…The inhibition of HIV-1 and HIV-2 replication and cytotoxicities of antiviral compounds were determined by the XTT {2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide} dye reduction method (2,41). The efficacies of antiviral compounds in inhibiting replication of HIV-1 NL4-3 and SIV mac 251 in MT-2 cells were monitored with levels of p24 and p27, respectively, as end points (6). Activities against the clinical HIV isolates were evaluated according to the ACTG protocol (19).…”

Section: Methodsmentioning

confidence: 99%

“…Two clones (S16 from the control virus and R74 from the resistant virus) were used to generate chimeric viruses by DNA transfection into HeLa-CD4 ϩ cells. The drug susceptibility of the chimeric virus was determined by an acute infection of MT-2 cells in the presence of various concentrations of drug followed by a p24 assay (6) or by transactivation of LTR-␤-gal following the infection of HeLa-CD4-LTR-␤-gal cells in the presence of compound (21). Three envelope clones (S16, S17, and S19) obtained from the wild-type RF virus and three envelope clones (R2, R4, and R74) obtained from the siamycin I-resistant virus were sequenced by using a set of internal primers and a DNA sequencing kit (Sequenase version 2; U.S. Biochemicals, Cleveland, Ohio).…”

Section: Methodsmentioning

confidence: 99%

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Characterization of siamycin I, a human immunodeficiency virus fusion inhibitor

Lin

Samanta

Bechtold

et al. 1996

Antimicrob Agents Chemother

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The human immunodeficiency virus (HIV) fusion inhibitor siamycin I, a 21-residue tricyclic peptide, was identified from a Streptomyces culture by using a cell fusion assay involving cocultivation of HeLa-CD4+ cells and monkey kidney (BSC-1) cells expressing the HIV envelope gp160. Siamycin I is effective against acute HIV type 1 (HIV-1) and HIV-2 infections, with 50% effective doses ranging from 0.05 to 5.7 microM, and the concentration resulting in a 50% decrease in cell viability in the absence of viral infection is 150 microM in CEM-SS cells. Siamycin I inhibits fusion between C8166 cells and CEM-SS cells chronically infected with HIV (50% effective dose of 0.08 microM) but has no effect on Sendai virus-induced fusion or murine myoblast fusion. Siamycin I does not inhibit gp120 binding to CD4 in either gp120- or CD4-based capture enzyme-linked immunosorbent assays. Inhibition of HIV-induced fusion by this compound is reversible, suggesting that siamycin I binds noncovalently. An HIV-1 resistant variant was selected by in vitro passage of virus in the presence of increasing concentrations of siamycin I. Drug susceptibility studies on a chimeric virus containing the envelope gene from the siamycin I-resistant variant indicate that resistance maps to the gp160 gene. Envelope-deficient HIV complemented with gp160 from siamycin I-resistant HIV also displayed a resistant phenotype upon infection of HeLa-CD4-LTR-beta-gal cells. A comparison of the DNA sequences of the envelope genes from the resistant and parent viruses revealed a total of six amino acid changes. Together these results indicate that siamycin I interacts with the HIV envelope protein.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Characterization of siamycin I, a human immunodeficiency virus fusion inhibitor

Lin

Samanta

Bechtold

et al. 1996

Antimicrob Agents Chemother

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“…The released mature viral particles contain a condensed core, consisting predominantly of the p24 capsid and p7 nucleocapsid proteins, surrounded by the viral membrane containing the p17 matrix protein. The viral maturation process can be blocked by the use of HIV-1 protease inhibitors, and as a result, the cell releases immature viral particles which are noninfectious (1,11,13,27,30,32,34,42).…”

mentioning

confidence: 99%

Conserved Cysteines of the Human Immunodeficiency Virus Type 1 Protease Are Involved in Regulation of Polyprotein Processing and Viral Maturation of Immature Virions

Davis

Yusa

Gillim

et al. 1999

J Virol

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We investigated the role of the two highly conserved cysteine residues, cysteines 67 and 95, of the human immunodeficiency virus type 1 (HIV-1) protease in regulating the activity of that protease during viral maturation. To this end, we generated four HIV-1 molecular clones: the wild type, containing both cysteine residues; a protease mutant in which the cysteine at position 67 was replaced by an alanine (C67A); a C95A protease mutant; and a double mutant (C67A C95A). When immature virions were produced in the presence of an HIV-1 protease inhibitor, KNI-272, and the inhibitor was later removed, limited polyprotein processing was observed for wild-type virion preparations over a 20-h period. Treatment of immature wild-type virions with the reducing agent dithiothreitol considerably improved the rate and extent of Gag processing, suggesting that the protease is, in part, reversibly inactivated by oxidation of the cysteine residues. In support of this, C67A C95A virions processed Gag up to fivefold faster than wild-type virions in the absence of a reducing agent. Furthermore, oxidizing agents, such as H2O2 and diamide, inhibited Gag processing of wild-type virions, and this effect was dependent on the presence of cysteine 95. Electron microscopy revealed that a greater percentage of double-mutant virions than wild-type virions developed a mature-like morphology on removal of the inhibitor. These studies provide evidence that under normal culture conditions the cysteines of the HIV-1 protease are susceptible to oxidation during viral maturation, thus preventing immature virions from undergoing complete processing following their release. This is consistent with the cysteines being involved in the regulation of viral maturation in cells under oxidative stress.

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“…The use of HIV protease as a potential target was validated in experiments which showed that mutations in the protease resulted in the production of defective, noninfectious virus (77,84,124). The demonstration of inhibitors with potent antiviral activity in cell culture-based assays (13,115,117,122,154) provided further evidence for HIV protease as a promising target for antiviral drug therapy. Data from subsequent clinical trials have demonstrated the safety and efficacy of HIV protease inhibitors and have, to date, led to the approval of four protease inhibitors: saquinavir (Invirase, Ro 31-8959), indinavir (Crixivan, MK-639), ritonavir (Norvir, ABT-538), and, most recently, nelfinavir (VIRACEPT, AG1343) ( Fig.…”

Section: Human Immunodeficiency Virus Proteasementioning

confidence: 99%

Protease Inhibitors as Antiviral Agents

1998

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SUMMARY Currently, there are a number of approved antiviral agents for use in the treatment of viral infections. However, many instances exist in which the use of a second antiviral agent would be beneficial because it would allow the option of either an alternative or a combination therapeutic approach. Accordingly, virus-encoded proteases have emerged as new targets for antiviral intervention. Molecular studies have indicated that viral proteases play a critical role in the life cycle of many viruses by effecting the cleavage of high-molecular-weight viral polyprotein precursors to yield functional products or by catalyzing the processing of the structural proteins necessary for assembly and morphogenesis of virus particles. This review summarizes some of the important general features of virus-encoded proteases and highlights new advances and/or specific challenges that are associated with the research and development of viral protease inhibitors. Specifically, the viral proteases encoded by the herpesvirus, retrovirus, hepatitis C virus, and human rhinovirus families are discussed.

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Antiviral properties of aminodiol inhibitors against human immunodeficiency virus and protease

Cited by 12 publications

References 39 publications

Characterization of siamycin I, a human immunodeficiency virus fusion inhibitor

Characterization of siamycin I, a human immunodeficiency virus fusion inhibitor

Conserved Cysteines of the Human Immunodeficiency Virus Type 1 Protease Are Involved in Regulation of Polyprotein Processing and Viral Maturation of Immature Virions

Protease Inhibitors as Antiviral Agents

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