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PDBsum entry 1hxw
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Hydrolase/hydrolase inhibitor PDB id
1hxw

 

 

 

 

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Contents
Protein chains
99 a.a. *
Ligands
RIT
Waters ×300
* Residue conservation analysis
PDB id:
1hxw
Name: Hydrolase/hydrolase inhibitor
Title: HIV-1 protease dimer complexed with a-84538
Structure: HIV-1 protease. Chain: a, b. Engineered: yes
Source: Human immunodeficiency virus 1. Organism_taxid: 11676. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Dimer (from PQS)
Resolution:
1.80Å     R-factor:   0.201    
Authors: C.H.Park,V.Nienaber,X.P.Kong
Key ref: D.J.Kempf et al. (1995). ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans. Proc Natl Acad Sci U S A, 92, 2484-2488. PubMed id: 7708670 DOI: 10.1073/pnas.92.7.2484
Date:
24-Jan-97     Release date:   04-Feb-98    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P12499  (POL_HV1Z2) -  Gag-Pol polyprotein from Human immunodeficiency virus type 1 group M subtype D (isolate Z2/CDC-Z34)
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1436 a.a.
99 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class 1: E.C.2.7.7.-  - ?????
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
   Enzyme class 2: E.C.2.7.7.49  - RNA-directed Dna polymerase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate
DNA(n)
 + 2'-deoxyribonucleoside 5'-triphosphate
 = DNA(n+1)
 + diphosphate
   Enzyme class 3: E.C.2.7.7.7  - DNA-directed Dna polymerase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate
DNA(n)
 + 2'-deoxyribonucleoside 5'-triphosphate
 = DNA(n+1)
 + diphosphate
   Enzyme class 4: E.C.3.1.-.-
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
   Enzyme class 5: E.C.3.1.13.2  - exoribonuclease H.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Exonucleolytic cleavage to 5'-phosphomonoester oligonucleotides in both 5'- to 3'- and 3'- to 5'-directions.
   Enzyme class 6: E.C.3.1.26.13  - retroviral ribonuclease H.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
   Enzyme class 7: E.C.3.4.23.16  - HIV-1 retropepsin.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Specific for a P1 residue that is hydrophobic, and P1' variable, but often Pro.
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
DOI no: 10.1073/pnas.92.7.2484 Proc Natl Acad Sci U S A 92:2484-2488 (1995)
PubMed id: 7708670  
 
 
ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans.
D.J.Kempf, K.C.Marsh, J.F.Denissen, E.McDonald, S.Vasavanonda, C.A.Flentge, B.E.Green, L.Fino, C.H.Park, X.P.Kong.
 
  ABSTRACT  
 
Examination of the structural basis for antiviral activity, oral pharmacokinetics, and hepatic metabolism among a series of symmetry-based inhibitors of the human immunodeficiency virus (HIV) protease led to the discovery of ABT-538, a promising experimental drug for the therapeutic intervention in acquired immunodeficiency syndrome (AIDS). ABT-538 exhibited potent in vitro activity against laboratory and clinical strains of HIV-1 [50% and HIV-2 (EC50 = 0.16 microM). Following a single 10-mg/kg oral dose, plasma concentrations in rat, dog, and monkey exceeded the in vitro antiviral EC50 for > 12 h. In human trials, a single 400-mg dose of ABT-538 displayed a prolonged absorption profile and achieved a peak plasma concentration in excess of 5 micrograms/ml. These findings demonstrate that high oral bioavailability can be achieved in humans with peptidomimetic inhibitors of HIV protease.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
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PDB code: 3nxu
19629548 J.Chen, S.Zhang, X.Liu, and Q.Zhang (2010).
Insights into drug resistance of mutations D30N and I50V to HIV-1 protease inhibitor TMC-114: free energy calculation and molecular dynamic simulation.
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20237088 M.N.Nalam, A.Ali, M.D.Altman, G.S.Reddy, S.Chellappan, V.Kairys, A.Ozen, H.Cao, M.K.Gilson, B.Tidor, T.M.Rana, and C.A.Schiffer (2010).
Evaluating the substrate-envelope hypothesis: structural analysis of novel HIV-1 protease inhibitors designed to be robust against drug resistance.
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PDB codes: 3gi4 3gi5 3gi6
20379971 N.S.Hamad, N.H.Al-Haidery, I.A.Al-Masoudi, M.Sabri, L.Sabri, and N.A.Al-Masoudi (2010).
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18951411 J.M.Sayer, and J.M.Louis (2009).
Interactions of different inhibitors with active-site aspartyl residues of HIV-1 protease and possible relevance to pepsin.
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18973272 M.Z.Dewan, M.Tomita, H.Katano, N.Yamamoto, S.Ahmed, M.Yamamoto, T.Sata, N.Mori, and N.Yamamoto (2009).
An HIV protease inhibitor, ritonavir targets the nuclear factor-kappaB and inhibits the tumor growth and infiltration of EBV-positive lymphoblastoid B cells.
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19364860 W.R.Lopes de Campos, D.Coopusamy, L.Morris, B.M.Mayosi, and M.Khati (2009).
Cytotoxicological analysis of a gp120 binding aptamer with cross-clade human immunodeficiency virus type 1 entry inhibition properties: comparison to conventional antiretrovirals.
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18384081 C.Borelli, E.Ruge, J.H.Lee, M.Schaller, A.Vogelsang, M.Monod, H.C.Korting, R.Huber, and K.Maskos (2008).
X-ray structures of Sap1 and Sap5: structural comparison of the secreted aspartic proteinases from Candida albicans.
  Proteins, 72, 1308-1319.
PDB codes: 2qzw 2qzx
  18820715 E.Lefebvre, and C.A.Schiffer (2008).
Resilience to resistance of HIV-1 protease inhibitors: profile of darunavir.
  AIDS Rev, 10, 131-142.  
18375506 G.Verkhivker, G.Tiana, C.Camilloni, D.Provasi, and R.A.Broglia (2008).
Atomistic simulations of the HIV-1 protease folding inhibition.
  Biophys J, 95, 550-562.  
17849388 K.Wittayanarakul, S.Hannongbua, and M.Feig (2008).
Accurate prediction of protonation state as a prerequisite for reliable MM-PB(GB)SA binding free energy calculations of HIV-1 protease inhibitors.
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19373036 M.N.Nalam, and C.A.Schiffer (2008).
New approaches to HIV protease inhibitor drug design II: testing the substrate envelope hypothesis to avoid drug resistance and discover robust inhibitors.
  Curr Opin HIV AIDS, 3, 642-646.  
18212102 T.Dekhtyar, T.I.Ng, L.Lu, S.Masse, D.A.DeGoey, W.J.Flosi, D.J.Grampovnik, L.L.Klein, D.J.Kempf, and A.Molla (2008).
Characterization of a novel human immunodeficiency virus type 1 protease inhibitor, A-790742.
  Antimicrob Agents Chemother, 52, 1337-1344.  
18004760 T.Hou, W.A.McLaughlin, and W.Wang (2008).
Evaluating the potency of HIV-1 protease drugs to combat resistance.
  Proteins, 71, 1163-1174.  
19373040 W.B.Bernstein, and P.A.Dennis (2008).
Repositioning HIV protease inhibitors as cancer therapeutics.
  Curr Opin HIV AIDS, 3, 666-675.  
17287285 D.Daelemans, R.Lu, E.De Clercq, and A.Engelman (2007).
Characterization of a replication-competent, integrase-defective human immunodeficiency virus (HIV)/simian virus 40 chimera as a powerful tool for the discovery and validation of HIV integrase inhibitors.
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17935445 L.L.Duan, Y.Tong, Y.Mei, Q.G.Zhang, and J.Z.Zhang (2007).
Quantum study of HIV-1 protease-bridge water interaction.
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17078039 R.Lledó-García, A.Nácher, L.Prats-García, V.G.Casabó, and M.Merino-Sanjuán (2007).
Bioavailability and pharmacokinetic model for ritonavir in the rat.
  J Pharm Sci, 96, 633-643.  
17474129 S.Chellappan, V.Kairys, M.X.Fernandes, C.Schiffer, and M.K.Gilson (2007).
Evaluation of the substrate envelope hypothesis for inhibitors of HIV-1 protease.
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16927344 A.K.Ghosh, P.Ramu Sridhar, N.Kumaragurubaran, Y.Koh, I.T.Weber, and H.Mitsuya (2006).
Bis-tetrahydrofuran: a privileged ligand for darunavir and a new generation of hiv protease inhibitors that combat drug resistance.
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16551874 A.Srirangam, R.Mitra, M.Wang, J.C.Gorski, S.Badve, L.Baldridge, J.Hamilton, H.Kishimoto, J.Hawes, L.Li, C.M.Orschell, E.F.Srour, J.S.Blum, D.Donner, G.W.Sledge, H.Nakshatri, and D.A.Potter (2006).
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16634628 J.C.Clemente, R.M.Coman, M.M.Thiaville, L.K.Janka, J.A.Jeung, S.Nukoolkarn, L.Govindasamy, M.Agbandje-McKenna, R.McKenna, W.Leelamanit, M.M.Goodenow, and B.M.Dunn (2006).
Analysis of HIV-1 CRF_01 A/E protease inhibitor resistance: structural determinants for maintaining sensitivity and developing resistance to atazanavir.
  Biochemistry, 45, 5468-5477.
PDB code: 2aqu
16436721 K.T.Andrews, D.P.Fairlie, P.K.Madala, J.Ray, D.M.Wyatt, P.M.Hilton, L.A.Melville, L.Beattie, D.L.Gardiner, R.C.Reid, M.J.Stoermer, T.Skinner-Adams, C.Berry, and J.S.McCarthy (2006).
Potencies of human immunodeficiency virus protease inhibitors in vitro against Plasmodium falciparum and in vivo against murine malaria.
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16555306 N.P.Todorov, C.L.Buenemann, and I.L.Alberts (2006).
De novo ligand design to an ensemble of protein structures.
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[Combination chemotherapy of S-1 +CPT-11 (q 4-5 w) for metastatic gastric cancer]
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Selecton: a server for detecting evolutionary forces at a single amino-acid site.
  Bioinformatics, 21, 2101-2103.  
16078135 C.J.Bachmeier, T.J.Spitzenberger, W.F.Elmquist, and D.W.Miller (2005).
Quantitative assessment of HIV-1 protease inhibitor interactions with drug efflux transporters in the blood-brain barrier.
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16127059 J.Yanchunas, D.R.Langley, L.Tao, R.E.Rose, J.Friborg, R.J.Colonno, and M.L.Doyle (2005).
Molecular basis for increased susceptibility of isolates with atazanavir resistance-conferring substitution I50L to other protease inhibitors.
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14990731 B.C.Logsdon, J.F.Vickrey, P.Martin, G.Proteasa, J.I.Koepke, S.R.Terlecky, Z.Wawrzak, M.A.Winters, T.C.Merigan, and L.C.Kovari (2004).
Crystal structures of a multidrug-resistant human immunodeficiency virus type 1 protease reveal an expanded active-site cavity.
  J Virol, 78, 3123-3132.
PDB codes: 1rpi 1rq9 1rv7
15502300 J.Brynda, P.Rezácová, M.Fábry, M.Horejsí, R.Stouracová, M.Soucek, M.Hradílek, J.Konvalinka, and J.Sedlácek (2004).
Inhibitor binding at the protein interface in crystals of a HIV-1 protease complex.
  Acta Crystallogr D Biol Crystallogr, 60, 1943-1948.
PDB code: 1u8g
15560801 J.Lindberg, D.Pyring, S.Löwgren, A.Rosenquist, G.Zuccarello, I.Kvarnström, H.Zhang, L.Vrang, B.Classon, A.Hallberg, B.Samuelsson, and T.Unge (2004).
Symmetric fluoro-substituted diol-based HIV protease inhibitors. Ortho-fluorinated and meta-fluorinated P1/P1'-benzyloxy side groups significantly improve the antiviral activity and preserve binding efficacy.
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PDB codes: 1ec0 1w5v 1w5w 1w5x 1w5y
14708020 S.Datta, and D.J.Grant (2004).
Crystal structures of drugs: advances in determination, prediction and engineering.
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The eukaryotic translation initiation factor 4GI is cleaved by different retroviral proteases.
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12502847 M.Prabu-Jeyabalan, E.A.Nalivaika, N.M.King, and C.A.Schiffer (2003).
Viability of a drug-resistant human immunodeficiency virus type 1 protease variant: structural insights for better antiviral therapy.
  J Virol, 77, 1306-1315.
PDB codes: 1mt7 1mt8 1mt9 1mtb 1n49
14689467 P.Khalili, E.Naimi, W.Y.Sun, E.E.Knaus, and L.I.Wiebe (2003).
Dose-dependent pharmacokinetics of 1-(2-deoxy-beta-D- ribofuranosyl)-2,4-difluoro-5-iodobenzene: a potential mimic of 5-iodo-2'-deoxyuridine.
  Biopharm Drug Dispos, 24, 385-395.  
14678601 Q.Zhao, H.Lu, D.Schols, E.De Clercq, and S.Jiang (2003).
Development of a cell-based enzyme-linked immunosorbent assay for high-throughput screening of HIV type 1 entry inhibitors targeting the coreceptor CXCR4.
  AIDS Res Hum Retroviruses, 19, 947-955.  
12604798 S.L.Morissette, S.Soukasene, D.Levinson, M.J.Cima, and O.Almarsson (2003).
Elucidation of crystal form diversity of the HIV protease inhibitor ritonavir by high-throughput crystallization.
  Proc Natl Acad Sci U S A, 100, 2180-2184.  
12767979 Y.C.Lin, Z.Beck, G.M.Morris, A.J.Olson, and J.H.Elder (2003).
Structural basis for distinctions between substrate and inhibitor specificities for feline immunodeficiency virus and human immunodeficiency virus proteases.
  J Virol, 77, 6589-6600.  
12004282 A.Sagir, M.Wettstein, M.Oette, A.Erhardt, and D.Häussinger (2002).
Budesonide-induced acute hepatitis in an HIV-positive patient with ritonavir as a co-medication.
  AIDS, 16, 1191-1192.  
11818491 A.Wlodawer (2002).
Rational approach to AIDS drug design through structural biology.
  Annu Rev Med, 53, 595-614.  
11873016 J.Weiss, J.Burhenne, K.D.Riedel, and W.E.Haefeli (2002).
Poor solubility limiting significance of in-vitro studies with HIV protease inhibitors.
  AIDS, 16, 674-676.  
11907228 N.Kaushik, A.Basu, P.Palumbo, R.L.Myers, and V.N.Pandey (2002).
Anti-TAR polyamide nucleotide analog conjugated with a membrane-permeating peptide inhibits human immunodeficiency virus type 1 production.
  J Virol, 76, 3881-3891.  
11901198 O.T.Keppler, F.J.Welte, T.A.Ngo, P.S.Chin, K.S.Patton, C.L.Tsou, N.W.Abbey, M.E.Sharkey, R.M.Grant, Y.You, J.D.Scarborough, W.Ellmeier, D.R.Littman, M.Stevenson, I.F.Charo, B.G.Herndier, R.F.Speck, and M.A.Goldsmith (2002).
Progress toward a human CD4/CCR5 transgenic rat model for de novo infection by human immunodeficiency virus type 1.
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12376954 S.Aquaro, P.Bagnarelli, T.Guenci, A.De Luca, M.Clementi, E.Balestra, R.Caliò, and C.F.Perno (2002).
Long-term survival and virus production in human primary macrophages infected by human immunodeficiency virus.
  J Med Virol, 68, 479-488.  
11866667 S.Rusconi, and S.La Seta Catamancio (2002).
HIV-1 protease inhibitors in development.
  Expert Opin Investig Drugs, 11, 387-395.  
12414928 S.W.Wang, and A.Aldovini (2002).
RNA incorporation is critical for retroviral particle integrity after cell membrane assembly of Gag complexes.
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11802090 A.Dasgupta, and P.C.Okhuysen (2001).
Pharmacokinetic and other drug interactions in patients with AIDS.
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11400666 G.Klebe (2001).
[Molecular modeling in the battle against AIDS. Drugs design in the development of substrate-like HIV protease inhibitors]
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10898681 B.S.Robinson, K.A.Riccardi, Y.F.Gong, Q.Guo, D.A.Stock, W.S.Blair, B.J.Terry, C.A.Deminie, F.Djang, R.J.Colonno, and P.F.Lin (2000).
BMS-232632, a highly potent human immunodeficiency virus protease inhibitor that can be used in combination with other available antiretroviral agents.
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11060719 J.A.Tavel (2000).
Ongoing trials in HIV protease inhibitors.
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10860901 J.J.Eron (2000).
HIV-1 protease inhibitors.
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11009599 M.J.Todd, I.Luque, A.Velázquez-Campoy, and E.Freire (2000).
Thermodynamic basis of resistance to HIV-1 protease inhibition: calorimetric analysis of the V82F/I84V active site resistant mutant.
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10770790 R.R.Speck, C.Flexner, C.J.Tian, and X.F.Yu (2000).
Comparison of human immunodeficiency virus type 1 Pr55(Gag) and Pr160(Gag-pol) processing intermediates that accumulate in primary and transformed cells treated with peptidic and nonpeptidic protease inhibitors.
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10737924 S.Piana, and P.Carloni (2000).
Conformational flexibility of the catalytic Asp dyad in HIV-1 protease: An ab initio study on the free enzyme.
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10775598 S.Sei, Q.E.Yang, D.O'Neill, K.Yoshimura, K.Nagashima, and H.Mitsuya (2000).
Identification of a key target sequence to block human immunodeficiency virus type 1 replication within the gag-pol transframe domain.
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10775609 Y.C.Lin, Z.Beck, T.Lee, V.D.Le, G.M.Morris, A.J.Olson, C.H.Wong, and J.H.Elder (2000).
Alteration of substrate and inhibitor specificity of feline immunodeficiency virus protease.
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10952574 Y.F.Gong, B.S.Robinson, R.E.Rose, C.Deminie, T.P.Spicer, D.Stock, R.J.Colonno, and P.F.Lin (2000).
In vitro resistance profile of the human immunodeficiency virus type 1 protease inhibitor BMS-232632.
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  10049266 A.Kiriyama, T.Nishiura, H.Yamaji, and K.Takada (1999).
Metabolic characterization of a tripeptide human immunodeficiency virus type 1 protease inhibitor, KNI-272, in rat liver microsomes.
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P-glycoprotein, secretory transport, and other barriers to the oral delivery of anti-HIV drugs.
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Ritonavir and saquinavir combination therapy for the treatment of HIV infection.
  AIDS, 13, 213-224.  
10837775 G.C.Williams, and P.J.Sinko (1999).
Oral absorption of the HIV protease inhibitors: a current update.
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10580399 H.Gatanaga, S.Aizawa, Y.Kikuchi, N.Tachikawa, I.Genka, S.Yoshizawa, Y.Yamamoto, A.Yasuoka, and S.Oka (1999).
Anti-HIV effect of saquinavir combined with ritonavir is limited by previous long-term therapy with protease inhibitors.
  AIDS Res Hum Retroviruses, 15, 1493-1498.  
10229651 K.C.Yeh, J.A.Stone, A.D.Carides, P.Rolan, E.Woolf, and W.D.Ju (1999).
Simultaneous investigation of indinavir nonlinear pharmacokinetics and bioavailability in healthy volunteers using stable isotope labeling technique: study design and model-independent data analysis.
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Human immunodeficiency virus protease inhibitors.
  Pharmacotherapy, 19, 35-59.  
10234158 M.Groettrup, and G.Schmidtke (1999).
Selective proteasome inhibitors: modulators of antigen presentation?
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  10543739 M.Nascimbeni, C.Lamotte, G.Peytavin, R.Farinotti, and F.Clavel (1999).
Kinetics of antiviral activity and intracellular pharmacokinetics of human immunodeficiency virus type 1 protease inhibitors in tissue culture.
  Antimicrob Agents Chemother, 43, 2629-2634.  
10380352 S.Thaisrivongs, and J.W.Strohbach (1999).
Structure-based discovery of Tipranavir disodium (PNU-140690E): a potent, orally bioavailable, nonpeptidic HIV protease inhibitor.
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10837769 X.Li, and W.K.Chan (1999).
Transport, metabolism and elimination mechanisms of anti-HIV agents.
  Adv Drug Deliv Rev, 39, 81.  
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In vitro selection and characterization of human immunodeficiency virus type 1 variants with increased resistance to ABT-378, a novel protease inhibitor.
  J Virol, 72, 7532-7541.  
  9585795 A.Cato, J.Cavanaugh, H.Shi, A.Hsu, J.Leonard, and R.Granneman (1998).
The effect of multiple doses of ritonavir on the pharmacokinetics of rifabutin.
  Clin Pharmacol Ther, 63, 414-421.  
  9661022 A.Cato, J.Qian, A.Hsu, B.Levy, J.Leonard, and R.Granneman (1998).
Multidose pharmacokinetics of ritonavir and zidovudine in human immunodeficiency virus-infected patients.
  Antimicrob Agents Chemother, 42, 1788-1793.  
  9797204 A.Hsu, G.R.Granneman, G.Cao, L.Carothers, A.Japour, T.El-Shourbagy, S.Dennis, J.Berg, K.Erdman, J.M.Leonard, and E.Sun (1998).
Pharmacokinetic interaction between ritonavir and indinavir in healthy volunteers.
  Antimicrob Agents Chemother, 42, 2784-2791.  
  9585800 A.Hsu, G.R.Granneman, G.Cao, L.Carothers, T.el-Shourbagy, P.Baroldi, K.Erdman, F.Brown, E.Sun, and J.M.Leonard (1998).
Pharmacokinetic interactions between two human immunodeficiency virus protease inhibitors, ritonavir and saquinavir.
  Clin Pharmacol Ther, 63, 453-464.  
9646869 A.Wlodawer, and J.Vondrasek (1998).
Inhibitors of HIV-1 protease: a major success of structure-assisted drug design.
  Annu Rev Biophys Biomol Struct, 27, 249-284.  
9727571 C.Cohen, D.A.Revicki, A.Nabulsi, P.W.Sarocco, and P.Jiang (1998).
A randomized trial of the effect of ritonavir in maintaining quality of life in advanced HIV disease. Advanced HIV Disease Ritonavir Study Group.
  AIDS, 12, 1495-1502.  
9543434 D.J.Kempf, R.A.Rode, Y.Xu, E.Sun, M.E.Heath-Chiozzi, J.Valdes, A.J.Japour, S.Danner, C.Boucher, A.Molla, and J.M.Leonard (1998).
The duration of viral suppression during protease inhibitor therapy for HIV-1 infection is predicted by plasma HIV-1 RNA at the nadir.
  AIDS, 12, F9-14.  
  9797791 D.Ouellet, A.Hsu, G.R.Granneman, G.Carlson, J.Cavanaugh, H.Guenther, and J.M.Leonard (1998).
Pharmacokinetic interaction between ritonavir and clarithromycin.
  Clin Pharmacol Ther, 64, 355-362.  
9723818 D.Ouellet, A.Hsu, J.Qian, C.S.Locke, C.J.Eason, J.H.Cavanaugh, J.M.Leonard, and G.R.Granneman (1998).
Effect of ritonavir on the pharmacokinetics of ethinyl oestradiol in healthy female volunteers.
  Br J Clin Pharmacol, 46, 111-116.  
  9835499 D.Ouellet, A.Hsu, J.Qian, J.E.Lamm, J.H.Cavanaugh, J.M.Leonard, and G.R.Granneman (1998).
Effect of fluoxetine on pharmacokinetics of ritonavir.
  Antimicrob Agents Chemother, 42, 3107-3112.  
9492772 D.W.Cameron, M.Heath-Chiozzi, S.Danner, C.Cohen, S.Kravcik, C.Maurath, E.Sun, D.Henry, R.Rode, A.Potthoff, and J.Leonard (1998).
Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. The Advanced HIV Disease Ritonavir Study Group.
  Lancet, 351, 543-549.  
9607960 F.Liard, J.Jaramillo, W.L.Paris, and C.Yoakim (1998).
Pharmacokinetic aspects of palinavir, an HIV protease inhibitor, in Sprague-Dawley rats.
  J Pharm Sci, 87, 782-785.  
  9835517 H.L.Sham, D.J.Kempf, A.Molla, K.C.Marsh, G.N.Kumar, C.M.Chen, W.Kati, K.Stewart, R.Lal, A.Hsu, D.Betebenner, M.Korneyeva, S.Vasavanonda, E.McDonald, A.Saldivar, N.Wideburg, X.Chen, P.Niu, C.Park, V.Jayanti, B.Grabowski, G.R.Granneman, E.Sun, A.J.Japour, J.M.Leonard, J.J.Plattner, and D.W.Norbeck (1998).
ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease.
  Antimicrob Agents Chemother, 42, 3218-3224.  
9715911 J.N.Champness, M.S.Bennett, F.Wien, R.Visse, W.C.Summers, P.Herdewijn, E.de Clerq, T.Ostrowski, R.L.Jarvest, and M.R.Sanderson (1998).
Exploring the active site of herpes simplex virus type-1 thymidine kinase by X-ray crystallography of complexes with aciclovir and other ligands.
  Proteins, 32, 350-361.
PDB codes: 1ki2 1ki3 1ki4 1ki5 1ki6 1ki7 1ki8 1kim
9527771 K.Hertogs, M.P.de Béthune, V.Miller, T.Ivens, P.Schel, A.Van Cauwenberge, C.Van Den Eynde, V.Van Gerwen, H.Azijn, M.Van Houtte, F.Peeters, S.Staszewski, M.Conant, S.Bloor, S.Kemp, B.Larder, and R.Pauwels (1998).
A rapid method for simultaneous detection of phenotypic resistance to inhibitors of protease and reverse transcriptase in recombinant human immunodeficiency virus type 1 isolates from patients treated with antiretroviral drugs.
  Antimicrob Agents Chemother, 42, 269-276.  
9789051 P.André, M.Groettrup, P.Klenerman, R.de Giuli, B.L.Booth, V.Cerundolo, M.Bonneville, F.Jotereau, R.M.Zinkernagel, and V.Lotteau (1998).
An inhibitor of HIV-1 protease modulates proteasome activity, antigen presentation, and T cell responses.
  Proc Natl Acad Sci U S A, 95, 13120-13124.  
9790666 P.J.Ala, E.E.Huston, R.M.Klabe, P.K.Jadhav, P.Y.Lam, and C.H.Chang (1998).
Counteracting HIV-1 protease drug resistance: structural analysis of mutant proteases complexed with XV638 and SD146, cyclic urea amides with broad specificities.
  Biochemistry, 37, 15042-15049.
PDB codes: 1bv7 1bv9 1bwa 1bwb
  9686647 S.C.Pettit, R.Sanchez, T.Smith, R.Wehbie, D.Derse, and R.Swanstrom (1998).
HIV type 1 protease inhibitors fail to inhibit HTLV-I Gag processing in infected cells.
  AIDS Res Hum Retroviruses, 14, 1007-1014.  
9726349 X.Sáez-Llorens, and O.Ramilo (1998).
Early experience with protease inhibitors in human immunodeficiency virus-infected children.
  Pediatr Infect Dis J, 17, 728-738.  
  9145841 A.Hsu, G.R.Granneman, G.Witt, C.Locke, J.Denissen, A.Molla, J.Valdes, J.Smith, K.Erdman, N.Lyons, P.Niu, J.P.Decourt, J.B.Fourtillan, J.Girault, and J.M.Leonard (1997).
Multiple-dose pharmacokinetics of ritonavir in human immunodeficiency virus-infected subjects.
  Antimicrob Agents Chemother, 41, 898-905.  
  9056009 D.J.Kempf, K.C.Marsh, G.Kumar, A.D.Rodrigues, J.F.Denissen, E.McDonald, M.J.Kukulka, A.Hsu, G.R.Granneman, P.A.Baroldi, E.Sun, D.Pizzuti, J.J.Plattner, D.W.Norbeck, and J.M.Leonard (1997).
Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by coadministration with ritonavir.
  Antimicrob Agents Chemother, 41, 654-660.  
  9145853 D.Lamarre, G.Croteau, E.Wardrop, L.Bourgon, D.Thibeault, C.Clouette, M.Vaillancourt, E.Cohen, C.Pargellis, C.Yoakim, and P.C.Anderson (1997).
Antiviral properties of palinavir, a potent inhibitor of the human immunodeficiency virus type 1 protease.
  Antimicrob Agents Chemother, 41, 965-971.  
9158869 D.Qasmi, E.de Rosny, L.René, B.Badet, I.Vergely, N.Boggetto, and M.Reboud-Ravaux (1997).
Synthesis of N-glyoxylyl peptides and their in vitro evaluation as HIV-1 protease inhibitors.
  Bioorg Med Chem, 5, 707-714.  
9443667 H.Uchida, Y.Maeda, and H.Mitsuya (1997).
HIV-1 protease does not play a critical role in the early stages of HIV-1 infection.
  Antiviral Res, 36, 107-113.  
9315877 J.Ermolieff, X.Lin, and J.Tang (1997).
Kinetic properties of saquinavir-resistant mutants of human immunodeficiency virus type 1 protease and their implications in drug resistance in vivo.
  Biochemistry, 36, 12364-12370.  
10837559 J.H.Lin (1997).
Human immunodeficiency virus protease inhibitors. From drug design to clinical studies.
  Adv Drug Deliv Rev, 27, 215-233.  
8989313 J.Vondrasek, C.P.van Buskirk, and A.Wlodawer (1997).
Database of three-dimensional structures of HIV proteinases.
  Nat Struct Biol, 4, 8.  
  9371335 K.T.Chong, and P.J.Pagano (1997).
In vitro combination of PNU-140690, a human immunodeficiency virus type 1 protease inhibitor, with ritonavir against ritonavir-sensitive and -resistant clinical isolates.
  Antimicrob Agents Chemother, 41, 2367-2373.  
  9145869 S.M.Poppe, D.E.Slade, K.T.Chong, R.R.Hinshaw, P.J.Pagano, M.Markowitz, D.D.Ho, H.Mo, R.R.Gorman, T.J.Dueweke, S.Thaisrivongs, and W.G.Tarpley (1997).
Antiviral activity of the dihydropyrone PNU-140690, a new nonpeptidic human immunodeficiency virus protease inhibitor.
  Antimicrob Agents Chemother, 41, 1058-1063.  
8673921 A.Molla, M.Korneyeva, Q.Gao, S.Vasavanonda, P.J.Schipper, H.M.Mo, M.Markowitz, T.Chernyavskiy, P.Niu, N.Lyons, A.Hsu, G.R.Granneman, D.D.Ho, C.A.Boucher, J.M.Leonard, D.W.Norbeck, and D.J.Kempf (1996).
Ordered accumulation of mutations in HIV protease confers resistance to ritonavir.
  Nat Med, 2, 760-766.  
  8738429 C.S.Dukes, T.J.Matthews, D.M.Lambert, G.B.Dreyer, S.R.Petteway, and J.B.Weinberg (1996).
Potent inhibition of HIV type 1 infection of mononuclear phagocytes by synthetic peptide analogs of HIV type 1 protease substrates.
  AIDS Res Hum Retroviruses, 12, 777-782.  
  8825619 H.Mo, M.Markowitz, P.Majer, S.K.Burt, S.V.Gulnik, L.I.Suvorov, J.W.Erickson, and D.D.Ho (1996).
Design, synthesis, and resistance patterns of MP-134 and MP-167, two novel inhibitors of HIV type 1 protease.
  AIDS Res Hum Retroviruses, 12, 55-61.  
  8970946 J.H.Condra, D.J.Holder, W.A.Schleif, O.M.Blahy, R.M.Danovich, L.J.Gabryelski, D.J.Graham, D.Laird, J.C.Quintero, A.Rhodes, H.L.Robbins, E.Roth, M.Shivaprakash, T.Yang, J.A.Chodakewitz, P.J.Deutsch, R.Y.Leavitt, F.E.Massari, J.W.Mellors, K.E.Squires, R.T.Steigbigel, H.Teppler, and E.A.Emini (1996).
Genetic correlates of in vivo viral resistance to indinavir, a human immunodeficiency virus type 1 protease inhibitor.
  J Virol, 70, 8270-8276.  
  8648711 L.Doyon, G.Croteau, D.Thibeault, F.Poulin, L.Pilote, and D.Lamarre (1996).
Second locus involved in human immunodeficiency virus type 1 resistance to protease inhibitors.
  J Virol, 70, 3763-3769.  
8894098 P.J.Tummino, J.V.Prasad, D.Ferguson, C.Nouhan, N.Graham, J.M.Domagala, E.Ellsworth, C.Gajda, S.E.Hagen, E.A.Lunney, K.S.Para, B.D.Tait, A.Pavlovsky, J.W.Erickson, S.Gracheck, T.J.McQuade, and D.J.Hupe (1996).
Discovery and optimization of nonpeptide HIV-1 protease inhibitors.
  Bioorg Med Chem, 4, 1401-1410.  
8643685 R.E.Rose, Y.F.Gong, J.A.Greytok, C.M.Bechtold, B.J.Terry, B.S.Robinson, M.Alam, R.J.Colonno, and P.F.Lin (1996).
Human immunodeficiency virus type 1 viral background plays a major role in development of resistance to protease inhibitors.
  Proc Natl Acad Sci U S A, 93, 1648-1653.  
7479972 J.N.Gnabre, J.N.Brady, D.J.Clanton, Y.Ito, J.Dittmer, R.B.Bates, and R.C.Huang (1995).
Inhibition of human immunodeficiency virus type 1 transcription and replication by DNA sequence-selective plant lignans.
  Proc Natl Acad Sci U S A, 92, 11239-11243.  
  7492104 M.Reedijk, C.A.Boucher, T.van Bommel, D.D.Ho, T.B.Tzeng, D.Sereni, P.Veyssier, S.Jurriaans, R.Granneman, and A.Hsu (1995).
Safety, pharmacokinetics, and antiviral activity of A77003, a C2 symmetry-based human immunodeficiency virus protease inhibitor.
  Antimicrob Agents Chemother, 39, 1559-1564.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.

 

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