Purification and biochemical characterization of recombinant simian immunodeficiency virus protease and comparison to human immunodeficiency virus type 1 protease

Grant, Stephan K.; Deckman, Ingrid C.; Minnich, Michael D.; Culp, Jeffrey S.; Franklin, Samuel; Dreyer, Geoffrey B.; Tomaszek, Thaddeus A.; Debouck, Christine; Meek, Thomas D.

doi:10.1021/bi00098a021

Cited by 51 publications

(58 citation statements)

References 55 publications

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“…However, the highest mean antigenemia level in the treated groups tended to be decreased and occurred progressively later in a dose-related manner, with a mean high concentration of 7.8 ng/ml occurring on day 10 in the untreated group, a mean high concentration of 5.1 ng/ml occurring on day 12 in the low-dose group, and a mean high concentration of 4.1 ng/ml occurring on day 14 in the high-dose group.…”

Section: Materuils and Methodsmentioning

confidence: 89%

“…Inhibitors of protease are also usually active against HIV-2 and SIV proteases (2,24,40). Recently, recombinant SIV protease has been purified, characterized, and compared with the HIV-1 protease (14). The SIV and HIV proteases produced similar digestion products from the HIV-1 precursor, and several synthetic peptide analogs that were inhibitory for the HIV-1 protease were also inhibitory for the SIV protease, indicating that the SIV macaque model could prove to be useful for the evaluation of the effects of protease inhibitors on retroviral infection in vivo.…”

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confidence: 99%

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Effects of U-75875, a peptidomimetic inhibitor of retroviral proteases, on simian immunodeficiency virus infection in rhesus monkeys

Martin

Soike

Murphey‐Corb

et al. 1994

Antimicrob Agents Chemother

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U-75875 inhibits human immunodeficiency virus types 1 and 2 and simian immunodeficiency virus (SlV) proteases and blocks Gag-Pol protein processing and viral maturation and replication in vitro. Rhesus monkeys were treated with vehicle alone or with formulated U-75875 at doses of 7 or 20 mg/kg of body weight per day for 26 days by continuous intravenous infusion beginning 6 h prior to intravenous inoculation with 10 monkey 50%1 infectious doses of SIV Delta B670, and the monkeys were monitored until death. The effects of treatment on the level of SIV p26 antigenemia, the infectious virus titer in serum, and the level of proviral DNA in blood mononuclear cells evaluated by PCR were assessed. SIV infection of the controls resulted in an initial viral antigenemia that began 5 to 10 days postinoculation (p.i.), reached peak values on days 10 to 14 p.i., and lasted for more than 15 days. Proviral DNA was detectable in peripheral blood mononuclear cells by 7 to 11 days p.i., reached the mean peak level by 11 days p.i., and remained at high levels through day 24 p.i. Infectious virus was detected in serum from all of the infected controls by 24 days p.i. Treatment with U-75875 for 26 days resulted in a dose-related delay in the day of the peak level of antigenemia (P = 0.034). The level of proviral DNA in peripheral blood mononuclear cells at 11 days p.i. was significantly decreased in a dose-related fashion in the treated monkeys (P c 0.048), with a delay in the attainment of the peak level of proviral DNA in the treated groups. The titer of infectious virus in the serum of the group treated with 20 mg/kg/day was significantly decreased on day 24 p.i. compared with that in the serum of controls (P = 0.046). Treatment with formulated U-75875 was well tolerated in rhesus monkeys and resulted in an inhibitory elfect on SIV in vivo.

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Section: Materuils and Methodsmentioning

confidence: 89%

mentioning

confidence: 99%

Effects of U-75875, a peptidomimetic inhibitor of retroviral proteases, on simian immunodeficiency virus infection in rhesus monkeys

Martin

Soike

Murphey‐Corb

et al. 1994

Antimicrob Agents Chemother

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“…Therefore, RSV and AMV protease sequences were removed, so that the remaining 36 sequences in the alignment are proteases from humans and simians. SIV protease has substrates homologous to HIV protease and has been shown to cleave HIV-1 polyprotein substrate in a manner similar to HIV-1 (Grant et al 1991). Thus, prediction based on this alignment should not be confounded by substratespecific residues as much as prediction based on the alignment containing RSV and AMV protease sequences.…”

Section: Comparison Of Sift With Blosum62 Predictions On Hiv-1 Proteamentioning

confidence: 99%

Predicting Deleterious Amino Acid Substitutions

Ng¹,

Henikoff²

2001

Genome Res.

2,333

2,014

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Many missense substitutions are identified in single nucleotide polymorphism (SNP) data and large-scale random mutagenesis projects. Each amino acid substitution potentially affects protein function. We have constructed a tool that uses sequence homology to predict whether a substitution affects protein function. SIFT, which sorts intolerant from tolerant substitutions, classifies substitutions as tolerated or deleterious. A higher proportion of substitutions predicted to be deleterious by SIFT gives an affected phenotype than substitutions predicted to be deleterious by substitution scoring matrices in three test cases. Using SIFT before mutagenesis studies could reduce the number of functional assays required and yield a higher proportion of affected phenotypes. SIFT may be used to identify plausible disease candidates among the SNPs that cause missense substitutions.

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“…SIV is susceptible to protease inhibitors that inhibit HIV-1 (1,3,25), but direct comparisons of these two viruses by using the same cell line with a quantitative infectivity assay have not been made. The proteases of HIV-1 and SIV have similar biochemical properties (11,27), but there are substantial differences in several amino acids in the active sites (47). The SIV protease was inhibited by one preclinical inhibitor, SB203386, but the K i for inhibition was 10 times higher than the K i for inhibition of the HIV-1 protease (20).…”

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confidence: 99%

Susceptibilities of Simian Immunodeficiency Virus to Protease Inhibitors

Giuffre¹,

Higgins²,

Buckheit

et al. 2003

Antimicrob Agents Chemother

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We used a focal infectivity assay with HeLa H1-JC.37 cells to directly compare susceptibilities of simian immunodeficiency virus (SIV) and human immunodeficiency virus type 1 (HIV-1) to protease inhibitors. SIVmac239 was inhibited by indinavir, saquinavir, and ritonavir, with 50% effective concentrations (means ؎ standard deviations) of 39 ؎ 8, 55 ؎ 3, and 13 ؎ 5 nM, respectively. The corresponding values for inhibition of HIV-1 were 66 ؎ 4, 47 ؎ 10, and 25 ؎ 14 nM, respectively.

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Purification and biochemical characterization of recombinant simian immunodeficiency virus protease and comparison to human immunodeficiency virus type 1 protease

Cited by 51 publications

References 55 publications

Effects of U-75875, a peptidomimetic inhibitor of retroviral proteases, on simian immunodeficiency virus infection in rhesus monkeys

Effects of U-75875, a peptidomimetic inhibitor of retroviral proteases, on simian immunodeficiency virus infection in rhesus monkeys

Predicting Deleterious Amino Acid Substitutions

Susceptibilities of Simian Immunodeficiency Virus to Protease Inhibitors

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