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Ac-Tyr-Arg-Ala-Arg-Val-Phe Nph-Val-Arg-Ala-Ala-Lys + H2O
Ac-Tyr-Arg-Ala-Arg-Val-Phe + Nph-Va-Arg-Ala-Ala-Lys
-
chromogenic substrate
-
-
?
AETFYVDGAA + H2O
AETF + YVDGAA
-
-
-
-
?
CTLNF + PISP + H2O
CTLNF + PISP
-
oligopeptide representing cleavage sites in HIV-1 Gag and Gag-Pol polyproteins, location of cleavage in PR/RT
-
-
?
CTLNFPISP + H2O
CTLNF + PISP
-
-
-
-
?
DKELYPLTSL + H2O
DKELY + PLTSL
-
oligopeptide representing cleavage sites in HIV-1 Gag and Gag-Pol polyproteins, location of cleavage in p6
-
-
?
EKGGNYPVQHV + H2O
EKGGNY + PVQHV
-
oligopeptide representing cleavage sites in HIV-1 Gag and Gag-Pol polyproteins, location of cleavage in MA/CA
-
-
?
GAG precursor protein F16 of HIV-1 + H2O
?
-
chemically synthesized aspartyl protease enzyme catalyzes specific processing of the recombinant 43-kDa protein
-
-
?
GAG precursor protein of HIV-2 + H2O
?
HIV-1 Gag-Pol poylprotein + H2O
?
-
site-specific proteolytic cleavage, protein precursors and peptides derived thereof
-
-
?
HIV-2 Gag-Pol poylprotein + H2O
?
-
site-specific proteolytic cleavage, protein precursors and peptides derived thereof
-
-
?
IPFAAAQQRK + H2O
IPFAA + AQQRK
IRKILFLDG + H2O
IRKIL + FLDG
-
oligopeptide representing cleavage sites in HIV-1 Gag and Gag-Pol polyproteins, location of cleavage in RT/IN
-
-
?
KARLMAEALK + H2O
KARLM + AEALK
KARVLAEAMS + H2O
KARVL + AEAMS
-
oligopeptide representing cleavage sites in HIV-1 Gag and Gag-Pol polyproteins, location of cleavage CA/X
-
-
?
KPRNFPVAQV + H2O
KPRNF + PVAQV
-
oligopeptide representing cleavage sites in HIV-1 Gag and Gag-Pol polyproteins, location of cleavage in NC/p6
-
-
?
Lys-Ala-Arg-Ile-Nle-Nph-Glu-Ala-Nle-NH2 + H2O
Lys-Ala-Arg-Ile-Nle + Nph-Glu-Ala-Nle-NH2
-
chromogenic substrate
-
-
?
Lys-Ala-Arg-Val-Nle-(4-nitrophenylalanine)-Glu-Ala-Nle + H2O
?
-
-
-
-
?
Lys-Ala-Arg-Val-Nle-Nph-Glu-Ala-Nle-NH2 + H2O
Lys-Ala-Arg-Val-Nle + Nph-Glu-Ala-Nle-NH2
-
the enzyme is highly active with peptide substrates containing variations of this cleavage sequence
-
-
?
Lys-Ala-Arg-Val-Nle-p-nitrophenylalanine-Glu-Ala-Nle-NH2 + H2O
?
-
-
-
-
?
MSLNLPVAKV + H2O
MSLNL + PVAKV
-
oligopeptide representing cleavage sites in HIV-1 Gag and Gag-Pol polyproteins, location of cleavage in TF/PR
-
-
?
myristylated p53-Gag precursor + H2O
?
-
-
-
-
?
NH2-ATLNFPSPW-COOH + H2O
?
-
-
-
-
?
p24-Gag protein + H2O
?
-
-
-
-
?
poly(A)-binding protein 1 + H2O
?
-
it is shown that HIV-1 and HIV-2 protease cleaves poly(A)-binding protein 1 directly at positions 237 and 477, separating the two first RNA-recognition motifs from the C-terminal domain of poly(A)-binding protein and additional cleavage site at position 410 is detected for HIV2-protease
-
-
?
RGLAAPQFSL + H2O
RGLAA + PQFSL
-
oligopeptide representing cleavage sites in HIV-1 Gag and Gag-Pol polyproteins, location of cleavage in TF/PR
-
-
?
RPQNFLQSRP + H2O
?
-
oligopeptide representing cleavage sites in HIV-1 Gag and Gag-Pol polyproteins, location of cleavage NC/p6
-
-
?
TATIMMQRGN + H2O
TATIM + MQRGN
-
oligopeptide representing cleavage sites in HIV-1 Gag and Gag-Pol polyproteins, location of cleavage X/NC
-
-
?
Val-Ser-Gln-Ala-Tyr-Pro-Ile-Val-Gln + H2O
Val-Ser-Gln-Ala-Tyr + Pro-Ile-Val-Gln
-
-
-
?
Val-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln + H2O
Val-Ser-Gln-Asn-Tyr + Pro-Ile-Val-Gln
-
-
-
?
Val-Ser-Gln-Cys-Tyr-Pro-Ile-Val-Gln + H2O
Val-Ser-Gln-Cys-Tyr + Pro-Ile-Val-Gln
-
-
-
?
Val-Ser-Gln-Gly-Tyr-Pro-Ile-Val-Gln + H2O
Val-Ser-Gln-Gly-Tyr + Pro-Ile-Val-Gln
-
-
-
?
Val-Ser-Gln-Ile-Tyr-Pro-Ile-Val-Gln + H2O
Val-Ser-Gln-Ile-Tyr + Pro-Ile-Val-Gln
-
-
-
?
Val-Ser-Gln-Leu-Tyr-Pro-Ile-Val-Gln + H2O
Val-Ser-Gln-Leu-Tyr + Pro-Ile-Val-Gln
-
-
-
?
Val-Ser-Gln-Phe-Tyr-Pro-Ile-Val-Gln + H2O
Val-Ser-Gln-Phe-Tyr + Pro-Ile-Val-Gln
-
-
-
?
Val-Ser-Gln-Thr-Tyr-Pro-Ile-Val-Gln + H2O
Val-Ser-Gln-Thr-Tyr + Pro-Ile-Val-Gln
-
-
-
?
Val-Ser-Gln-Val-Tyr-Pro-Ile-Val-Gln + H2O
Val-Ser-Gln-Val-Tyr + Pro-Ile-Val-Gln
-
-
-
?
VLQNYPIVQ + H2O
VLQNY + PIVQ
VSQLYPIVQ + H2O
VSQLY + PIVQ
VSQNYPIVQ + H2O
?
-
oligopeptide representing cleavage sites in HIV-1 Gag and Gag-Pol polyproteins, location of cleavage MA/CA
-
-
?
VSQNYPIVQ + H2O
VSQNY + PIVQ
-
oligopeptide substrate
-
-
?
VSQNYPLVQ + H2O
VSQNY + PLVQ
-
oligopeptide substrate
-
-
?
VSQVYPIVQ + H2O
VSQVY + PIVQ
-
peptide represents a variation of HIV-1 MA/CA cleavage site
-
-
?
VVQNYPIVQ + H2O
VVQNY + PIVQ
-
peptide represents a variation of HIV-1 MA/CA cleavage site
-
-
?
YVSQNFPIVQNR + H2O
YVSQNF + PIVQNR
-
synthetic peptide substrate based on the Ma/Ca cleavage site of HIV-1 Gag
-
-
?
additional information
?
-
GAG precursor protein of HIV-2 + H2O
?
-
-
644057, 644058, 644059, 644060, 644062, 644063, 644064, 644065, 644066, 644067, 644068, 644069 -
-
?
GAG precursor protein of HIV-2 + H2O
?
-
protease is responsible for processing of the gag structural polyprotein and the release of virally encoded enzymes like protease, reverse transcriptase and integrase from the gag-pol fusion protein
-
-
?
IPFAAAQQRK + H2O
IPFAA + AQQRK
-
oligopeptide representing cleavage sites in HIV-1 Gag and Gag-Pol polyproteins, location of cleavage in X/NC
-
-
?
IPFAAAQQRK + H2O
IPFAA + AQQRK
-
peptide represents the HIV-2 cleavage site p2/NC
-
-
?
KARLMAEALK + H2O
KARLM + AEALK
-
oligopeptide representing cleavage sites in HIV-1 Gag and Gag-Pol polyproteins, location of cleavage in MA/CA
-
-
?
KARLMAEALK + H2O
KARLM + AEALK
-
peptide represents the HIV-2 cleavage site CA/p2
-
-
?
VLQNYPIVQ + H2O
VLQNY + PIVQ
-
oligopeptide substrate
-
-
?
VLQNYPIVQ + H2O
VLQNY + PIVQ
-
peptide represents a variation of HIV-1 MA/CA cleavage site
-
-
?
VSQLYPIVQ + H2O
VSQLY + PIVQ
-
oligopeptide substrate
-
-
?
VSQLYPIVQ + H2O
VSQLY + PIVQ
-
peptide represents a variation of HIV-1 MA/CA cleavage site
-
-
?
additional information
?
-
-
oligopeptide III VLAEAM.SQVTN, oligopeptide V TERQAN.FLGKI, oligopeptide VII ESFRSG.VETTT and oligopeptide XVI DRQAG.FLGLG are not hydrolyzed, oligopeptide IX VSFNF PQITL and oligopeptide XXI IRQVL FLEKI Km less than 0.01 mM
-
-
?
additional information
?
-
-
catalyzes hydrolysis of Phe-Pro, Tyr-Pro and other peptide bonds in the gag and gag-pol polyproteins
-
-
?
additional information
?
-
-
cleavage sites identified by amino-terminal sequence analysis are F3-S4, Y14-I15, G35-I36, G52-F53, M76-T77, L90-T91
-
-
?
additional information
?
-
amino acid preferences for the critical P2' substrate binding subsite in type 1 cleavage sites, molecular modeling and phylogenetic comparison, overview
-
-
?
additional information
?
-
-
the enzyme prefers the cleavage site sequence VSQNY*PIVQ with Glu being preferred at the P2' site
-
-
?
additional information
?
-
-
enzyme undergoes autoproteolysis at pH 3 at the G35/I36 site
-
-
?
additional information
?
-
PR2 recognizes various non-homologous substrates (Gag and Pol polyproteins) at several cleavage sites and protease inhibitors
-
-
?
additional information
?
-
-
PR2 recognizes various non-homologous substrates (Gag and Pol polyproteins) at several cleavage sites and protease inhibitors
-
-
?
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(2R,4S,5S)-6-cyclohexyl-5-(3,3-dimethylbutanamido)-4-hydroxy-2-isopropyl-N-((2S,3R)-3-methyl-1-oxo-1-(phenethylamino)pentan-2-yl)hexanamide
-
synthetic inhibitor 4
(hydroxyethyl)amide isostere
-
-
2,6-dimethylbenzyl (2S,3R)-4-((2S,4R)-2-(tert-butylcarbamoyl)-4-(4,6-dimethylpyrimidin-2-ylthio)piperidin-1-yl)-3-hydroxy-1-phenylbutan-2-ylcarbamate
-
hydroxyethylamine dipeptide isostere inhibitor 3
2,6-dimethylbenzyl (2S,3R)-4-((2S,4R)-2-(tert-butylcarbamoyl)-4-(pyridin-3-ylmethoxy)piperidin-1-yl)-3-hydroxy-1-phenylbutan-2-ylcarbamate
-
hydroxyethylamine dipeptide isostere inhibitor 5
2,6-dimethylbenzyl (2S,3R)-4-((2S,4R)-2-(tert-butylcarbamoyl)-4-(pyridin-3-ylthio)piperidin-1-yl)-3-hydroxy-1-phenylbutan-2-ylcarbamate
-
hydroxyethylamine dipeptide isostere inhibitor 2
2,6-dimethylbenzyl (2S,3R)-4-((2S,4R)-2-(tert-butylcarbamoyl)-4-(pyridin-4-ylsulfonyl)piperidin-1-yl)-3-hydroxy-1-phenylbutan-2-ylcarbamate
-
hydroxyethylamine dipeptide isostere inhibitor 4
2,6-dimethylbenzyl (2S,3R)-4-((2S,4R)-2-(tert-butylcarbamoyl)-4-(pyridin-4-ylthio)piperidin-1-yl)-3-hydroxy-1-phenylbutan-2-ylcarbamate
-
hydroxyethylamine dipeptide isostere inhibitor 1
benzyl (S)-1-((2S,3R)-4-((R)-4-(tert-butylcarbamoyl)thiazolidin-3-yl)-3-hydroxy-1-phenylbutan-2-ylamino)-4-amino-1,4-dioxobutan-2-ylcarbamate
-
synthetic inhibitor 1
benzyl (S)-1-((2S,3R)-4-((S) -2-(tert-butylcarbamoyl)indolin-1-yl)-3-hydroxy-1-phenylbutan-2-ylamino)-4-amino-1,4-dioxobutan-2-ylcarbamate
-
synthetic inhibitor 2
CTLNF-PSI[CH2-NH]-PISP
-
competitive inhibition
H2O2
-
inactivated after oxidation at the dimer interface, activity can be partly restored with methionine sulphoxide reductase
monoclonal antibody 1696
-
-
-
N-((S)-1-((2S,3R)-4-((2S,4R)-2-(tert-butylcarbamoyl)-4-(pyridin-3-ylmethoxy)piperidin-1-yl)-3-hydroxy-1-phenylbutan-2-ylamino)-3-methyl-1-oxobutan-2-yl)quinoline-2-carboxamide
-
hydroxyethylamine dipeptide isostere inhibitor 8
N-((S)-1-((2S,3R)-4-((2S,4R)-2-(tert-butylcarbamoyl)-4-(pyridin-3-ylmethylthio)piperidin-1-yl)-3-hydroxy-1-phenylbutan-2-ylamino)-3-methyl-1-oxobutan-2-yl)quinoline-2-carboxamide
-
hydroxyethylamine dipeptide isostere inhibitor 6
N-((S)-1-((2S,3R)-4-((2S,4R)-2-(tert-butylcarbamoyl)-4-(pyridin-3-ylthio)piperidin-1-yl)-3-hydroxy-1-phenylbutan-2-ylamino)-3-methyl-1-oxobutan-2-yl)quinoline-2-carboxamide
-
hydroxyethylamine dipeptide isostere inhibitor 7
N-((S)-1-((2S,3R)-4-((3S,4aS,8aS)-3-(tert-butylcarbamoyl)-octahydroisoquinolin-2(1H)-yl)-3-hydroxy-1-phenylbutan-2-ylamino)-4-amino-1,4-dioxobutan-2-yl)quinoline-3-carboxamide
-
synthetic inhibitor 3
Phe-Val-Phe-psi-[CH2NH]-Leu-Glu-Ile-amide
-
-
tert-butyl (2S,3S)-5-(((2S,3R)-3-methyl-1-oxo-1-(phenethylamino)pentan-2-yl)carbamoyl)-1-cyclohexyl-3-hydroxy-6-methylheptan-2-ylcarbamate
-
synthetic inhibitor 6
tert-butyl (2S,3S,5R)-5-(((2S,3R)-3-methyl-1-oxo-1-(phenethylamino)pentan-2-yl)carbamoyl)-1-cyclohexyl-3-hydroxy-6-methylheptan-2-ylcarbamate
-
synthetic inhibitor 5
VSFNF-PSI[CH2-NH]-PQITL
-
competitive inhibition
acetyl-pepstatin
-
common inhibitor of aspartic proteases
amprenavir
inhibitor binds less strongly to HIV-2 protease than to HIV-2 protease due to a reduction of the van der Waals interactions. Inhibitor binding tends to make the flaps of PR2 close and the one of PR1 open
darunavir
inhibitor binds less strongly to HIV-2 protease than to HIV-2 protease due to a reduction of the van der Waals interactions. Inhibitor binding tends to make the flaps of PR2 close and the one of PR1 open
indinavir
-
n(2(R)hydroxy-1(S)indanyl)-5-((2(S)tertiarybutylaminocarbonyl)4(3pyridylmethyl)piperazino)-4(S)-hydroxy-2(R)-phenylmethylpentanamide, piperazino, L-735,524, potent orally bioavailable inhibitor, currently in a phase II clinical trial
lopinavir
-
activity of lopinavir against three strains of HIV-2 is assessed and compared to activity against a reference HIV-1 strain. Lopinavir demonstrates activity similar to that observed against HIV-1 in two HIV-2 strains (HIV-2MS and HIV-2CBL-23) tested. 10fold reduced susceptibility is observed using strain HIV-2CDC310319
saquinavir
-
-
additional information
-
no inhibition with 1,10-phenanthroline and phenylmethylsulfonylfluoride or EDTA
-
additional information
analysis of the differences of binding patterns between the two type HIV proteases, HIV-1 protease and HIV-2 protease, and the two inhibitors darunavir and amprenavir using the interaction entropy (IE) method for the entropy change calculation combined with the polarized force field. The functional role of protonation states in the two HIV-2 complexes is investigated revealing that the protonated OD1 atom of Asp25' in B chain is the optimal choice. The bridging water W301 is unfavorable to the binding of HIV-2 complexes, in contrast to HIV-1 protease complexes. The volume of pocket, B-factor of Calpha atoms and the distance of flap tip in HIV-2 complexes are smaller than that of HIV-1 consistently. Predicated hot-spot residues (Ala28/Ala28', Ile50/Ile50', and Ile84/Ile84') are nearly same in the four systems. The contribution to the free energy of Asp30 residue is more favorable in HIV-1 system than in HIV-2 system. Molecular dynamics simulation and binding free energy calculations, and protonation states of the enzymes, overview
-
additional information
comparison of 19 ligand-bound enzyme structures to localize structural asymmetry specific to particular ligands and the one conserved across most PR2 structures, detailed overview. Localization of structural variability induced by PR2 intrinsic flexibility
-
additional information
-
comparison of 19 ligand-bound enzyme structures to localize structural asymmetry specific to particular ligands and the one conserved across most PR2 structures, detailed overview. Localization of structural variability induced by PR2 intrinsic flexibility
-
additional information
HIV-2 exhibits intrinsic resistance to most FDA-approved HIV-1 protease inhibitors, retaining clinically useful susceptibility only to lopinavir, darunavir, and saquinavir. Structural rationale for intrinsic HIV-2 PI resistance. No inhibition by amprenavir, atazanavir, indinavir, nelfinavir, ritonavir, and tipranavir. Phenotypic protease inhibitor sensitivities of wild-type HIV-1, wild-type HIV-2, and mutant HIV-2 strains, overview
-
additional information
-
HIV-2 exhibits intrinsic resistance to most FDA-approved HIV-1 protease inhibitors, retaining clinically useful susceptibility only to lopinavir, darunavir, and saquinavir. Structural rationale for intrinsic HIV-2 PI resistance. No inhibition by amprenavir, atazanavir, indinavir, nelfinavir, ritonavir, and tipranavir. Phenotypic protease inhibitor sensitivities of wild-type HIV-1, wild-type HIV-2, and mutant HIV-2 strains, overview
-
additional information
HIV-2 protease (PR2) is naturally resistant to most FDA approved HIV-1 protease inhibitors (PIs), a major antiretroviral class. Comparison of the HIV-1 protease (PR1) and HIV-2 protease (PR2) binding pockets extracted from structures complexed with 12 ligands, overview. Structural comparison of PR1 and PR2 pockets highlight structural changes induced by their sequence variations. PR2 pockets are more hydrophobic with more oxygen atoms and fewer nitrogen atoms than PR1 pockets. Specifically, substitutions at residues 31, 46, and 82 induce structural changes in their main-chain atoms that can affect PI binding in PR2. Substitutions in the PR1 and PR2 pockets can modify PI binding and flap flexibility, which might underlie PR2 resistance against PIs
-
additional information
-
HIV-2 protease (PR2) is naturally resistant to most FDA approved HIV-1 protease inhibitors (PIs), a major antiretroviral class. Comparison of the HIV-1 protease (PR1) and HIV-2 protease (PR2) binding pockets extracted from structures complexed with 12 ligands, overview. Structural comparison of PR1 and PR2 pockets highlight structural changes induced by their sequence variations. PR2 pockets are more hydrophobic with more oxygen atoms and fewer nitrogen atoms than PR1 pockets. Specifically, substitutions at residues 31, 46, and 82 induce structural changes in their main-chain atoms that can affect PI binding in PR2. Substitutions in the PR1 and PR2 pockets can modify PI binding and flap flexibility, which might underlie PR2 resistance against PIs
-
additional information
the ligand binding site is located at the interface between the two monomers and includes the catalytic triplet, Asp-Thr-Gly, conserved in all aspartic proteases. Detection of structural local asymmetry in the PR2 dimer complexed with a diversified set of ligands, quantification of the structural asymmetry of the PR2 set, overview
-
additional information
-
the ligand binding site is located at the interface between the two monomers and includes the catalytic triplet, Asp-Thr-Gly, conserved in all aspartic proteases. Detection of structural local asymmetry in the PR2 dimer complexed with a diversified set of ligands, quantification of the structural asymmetry of the PR2 set, overview
-
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0.000016 - 0.001112
indinavir
0.000004 - 0.0166
lopinavir
0.000064 - 0.002564
nelfinavir
0.1472 - 0.554
saquinavir
0.000145 - 0.004436
tipranavir
0.000098
amprenavir
Human immunodeficiency virus 2
-
mutant V62A/L99F
0.00044
amprenavir
Human immunodeficiency virus 2
-
wild-type
0.000528
amprenavir
Human immunodeficiency virus 2
-
mutant I82L
0.000965
amprenavir
Human immunodeficiency virus 2
-
mutant I82F
1
amprenavir
Human immunodeficiency virus 2
-
mutant I50V, value above 10
1
amprenavir
Human immunodeficiency virus 2
-
mutant I54M/L84V: value above 10
1
amprenavir
Human immunodeficiency virus 2
-
mutant I54M/L90M: value above 10
1
amprenavir
Human immunodeficiency virus 2
-
mutant I54M/L99F: value above 10
1
amprenavir
Human immunodeficiency virus 2
-
mutant I54M: value above 10
0.000016
indinavir
Human immunodeficiency virus 2
-
wild-type
0.000064
indinavir
Human immunodeficiency virus 2
-
mutant I82L
0.000072
indinavir
Human immunodeficiency virus 2
-
mutant I50V
0.000143
indinavir
Human immunodeficiency virus 2
-
mutant V62A/L99F
0.000236
indinavir
Human immunodeficiency virus 2
-
mutant I54M
0.000388
indinavir
Human immunodeficiency virus 2
-
mutant I54M/L84V
0.000544
indinavir
Human immunodeficiency virus 2
-
mutant I82F
0.000825
indinavir
Human immunodeficiency virus 2
-
mutant I54M/L99F
0.001112
indinavir
Human immunodeficiency virus 2
-
mutant I54M/L90M
0.000004
lopinavir
Human immunodeficiency virus 2
-
wild-type
0.000075
lopinavir
Human immunodeficiency virus 2
-
mutant I82L
0.000145
lopinavir
Human immunodeficiency virus 2
-
mutant I82F
0.000203
lopinavir
Human immunodeficiency virus 2
-
mutant I50V
0.000375
lopinavir
Human immunodeficiency virus 2
-
mutant I54M/L84V
0.000414
lopinavir
Human immunodeficiency virus 2
-
mutant I54M/L99F
0.000481
lopinavir
Human immunodeficiency virus 2
-
mutant I54M
0.000496
lopinavir
Human immunodeficiency virus 2
-
mutant V62A/L99F
0.000524
lopinavir
Human immunodeficiency virus 2
-
mutant I54M/L90M
0.0111
lopinavir
Human immunodeficiency virus 2
-
mutant L99F
0.0125
lopinavir
Human immunodeficiency virus 2
-
mutant L90M
0.0166
lopinavir
Human immunodeficiency virus 2
-
-
0.000064
nelfinavir
Human immunodeficiency virus 2
-
wild-type
0.000106
nelfinavir
Human immunodeficiency virus 2
-
mutant I82L
0.000132
nelfinavir
Human immunodeficiency virus 2
-
mutant I50V
0.000244
nelfinavir
Human immunodeficiency virus 2
-
mutant I82F
0.000624
nelfinavir
Human immunodeficiency virus 2
-
mutant I54M
0.000961
nelfinavir
Human immunodeficiency virus 2
-
mutant V62A/L99F
0.001747
nelfinavir
Human immunodeficiency virus 2
-
mutant I54M/L84V
0.002241
nelfinavir
Human immunodeficiency virus 2
-
mutant I54M/L99F
0.002564
nelfinavir
Human immunodeficiency virus 2
-
mutant I54M/L90M
0.1472
saquinavir
Human immunodeficiency virus 2
-
mutant L99F
0.1497
saquinavir
Human immunodeficiency virus 2
-
-
0.554
saquinavir
Human immunodeficiency virus 2
-
mutant L90M
0.000145
tipranavir
Human immunodeficiency virus 2
-
mutant I54M/L90M
0.00016
tipranavir
Human immunodeficiency virus 2
-
wild-type
0.000306
tipranavir
Human immunodeficiency virus 2
-
mutant I82F
0.000316
tipranavir
Human immunodeficiency virus 2
-
mutant I50V
0.000524
tipranavir
Human immunodeficiency virus 2
-
mutant V62A/L99F
0.001106
tipranavir
Human immunodeficiency virus 2
-
mutant I54M
0.002028
tipranavir
Human immunodeficiency virus 2
-
mutant I54M/L84V
0.002908
tipranavir
Human immunodeficiency virus 2
-
mutant I54M/L99F
0.004436
tipranavir
Human immunodeficiency virus 2
-
mutant I82L
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D25N
-
inactive mutant forms a dimer
DELTA96-99
-
dimer interface mutations such as a deletion of the C-terminal residues 96-99 (PR21-95), drastically increase the Kd. Deletion mutant consists predominantly of folded monomers. Addition of 2fold excess active-site inhibitor does not promote dimerization
E37K
-
mutation significantly retards autoproteolytic cleavage during expression. Mutant shows a higher dimer dissociation constant, Kd, compared to wild-type. Km and kcat values for substrate Lys-Ala-Arg-Val-Nle-(4-nitrophenylalanine)-Glu-Ala-Nle comparable to wild-type
I32V
site-directed mutagenesis, mutation analogous to wild-type HIV-1 protease sequence (EC 3.4.23.16). The mutation increases the susceptibility of HIV-2 to multiple protease inhibitors
I50V
-
IC50 (mM): value above 10 (amprenavir), 0.000072 (idinavir), 0.000132 (nelfinavir), 0.000316 (tipranavir), 0.000203 (lopinavir)
I54M/I84V
-
IC50 (mM): value above 10 (amprenavir), 0.000388 (idinavir), 0.001747 (nelfinavir), 0.002028 (tipranavir), 0.000375 (lopinavir)
I54M/L90M
-
IC50 (mM): value above 10 (amprenavir), 0.001112 (idinavir), 0.002564 (nelfinavir), 0.000145 (tipranavir), 0.000524 (lopinavir)
I54M/L99F
-
IC50 (mM): value above 10 (amprenavir), 0.000825 (idinavir), 0.002241 (nelfinavir), 0.002908 (tipranavir), 0.000414 (lopinavir)
I82F
-
IC50 (mM): 0.000965 (amprenavir), 0.000544 (idinavir), 0.000244 (nelfinavir), 0.000306 (tipranavir), 0.000145 (lopinavir)
I82L
-
IC50 (mM): 0.000528 (amprenavir), 0.000064 (idinavir), 0.000106 (nelfinavir), 0.00016 (tipranavir), 0.000075 (lopinavir)
I82L/L99F
-
IC50 (mM): 0.000098 (amprenavir), 0.000143 (idinavir), 0.000961 (nelfinavir), 0.000524 (tipranavir), 0.000496 (lopinavir)
I82V
site-directed mutagenesis, mutation analogous to wild-type HIV-1 protease sequence (EC 3.4.23.16)
K45R
-
mutant is resistant toward HIV-2 protease inhibitor lopinavir and saquinavir in yeast
K57L
site-directed mutagenesis, the mutation is experimentally introduced to help the crystallographic process
L90M
-
IC50: 0.0125 (lopinavir), 0.554 (saquinavir), L90M mutation present in primary HIV-2 isolate, modifies the HIV-2 protease susceptibility to saquinavir but not lopinavir
L99F
-
IC50: 0.0111 (lopinavir), 0.1472 (saquinavir)
M76L
site-directed mutagenesis, mutation analogous to wild-type HIV-1 protease sequence (EC 3.4.23.16). The mutation increases the susceptibility of HIV-2 to multiple protease inhibitors
M76V
-
mutant is resistant toward HIV-2 protease inhibitor lopinavir and saquinavir in yeast
T26A
-
dimer interface mutations in the active site of PR2 drastically increase the Kd. T26A consists predominantly of folded monomers. Addition of 2fold excess active-site inhibitor promotes dimerization of mutant PR2T26A
V47A/D17N
-
passage of HIV-2MS with increasing concentrations of lopinavir selects mutations V47A and D17N in the HIV-2 protease gene. Introduction of both 17N and 47A either individually or together into HIV-2ROD molecular infectious clones shows that the single V47A substitution in HIV-2 results in a substantial reduction in susceptibility to lopinavir. This mutant retains wild-type susceptibility to other proteinase inhibitors and is hypersusceptible to atazanavir and saquinavir
V47I
site-directed mutagenesis, mutation analogous to wild-type HIV-1 protease sequence (EC 3.4.23.16). The mutation increases the susceptibility of HIV-2 to multiple protease inhibitors
V47I/M76L/I32V/I82V
site-directed mutagenesis, mutation analogous to wild-type HIV-1 protease sequence (EC 3.4.23.16). The combination of the four amino acid changes in HIV-2 protease confers a pattern of protease inhibitor susceptibility comparable to that of HIV-1
V71I, L90M, I89V
-
most frequently detected mutations within PR selected under antiretroviral drug therapy in a clinical cohort study with 25 patients treated with antiretroviral therapy
I54M
-
IC50 (mM): value above 10 (amprenavir), 0.000236 (idinavir), 0.000624 (nelfinavir), 0.001106 (tipranavir), 0.000481 (lopinavir)
I54M
-
mutant is resistant toward HIV-2 protease inhibitor lopinavir and saquinavir in yeast
additional information
-
construction of a hybrid gene with the viral reverse transcriptase, constuction of a hybrid comprising HIV-1 and HIV-2 retropepsin, overview
additional information
-
within 10 to 15 weeks of serial passage, three major mutations: I54M, I82F, and L90M arise in HIV-2 viral cultures exposed to amprenavir, nelfinavir, indinavir, whereas I82L is selected with tripranavir. After 25 weeks, other cultures develop I50V and I84V mutations. The acquisition of the I54M, I84V, L90M, and L99F mutations result in multi-PI-resistant viruses, conferring 10fold to more than 100fold resistance
additional information
construction of HIV-2ROD9 molecular clones containing amino acid changes corresponding to wild-type HIV-1 amino acids (I32V, V47I, M76L, and I82V) either individually or together (clone PRDELTA4) and comparison of the phenotypic sensitivities (50% effective concentration [EC50]) of mutant and wild-type viruses to nine FDA-approved protease inhibitors, overview. Clone PRDELTA4 show protease inhibitor susceptibility equivalent to or greater than that of HIV-1 for all protease inhibitors
additional information
-
construction of HIV-2ROD9 molecular clones containing amino acid changes corresponding to wild-type HIV-1 amino acids (I32V, V47I, M76L, and I82V) either individually or together (clone PRDELTA4) and comparison of the phenotypic sensitivities (50% effective concentration [EC50]) of mutant and wild-type viruses to nine FDA-approved protease inhibitors, overview. Clone PRDELTA4 show protease inhibitor susceptibility equivalent to or greater than that of HIV-1 for all protease inhibitors
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