Showing drug card for Lopinavir (DB01601)

• EXPT00388

• Approved
• Small Molecule

1. ABT-378
2. LPV

1. Aluviran
2. Koletra

1. Kaletra (Lopinavir + Ritonavir)

• Anti-HIV Agents
• HIV Protease Inhibitors

• Avoid St.John's Wort.
• Take with food.

1. Wikipedia
2. RxList
3. PDRhealth

• Human Immunodeficiency Virus

1. Cytochrome P450 3A4 (CYP3A4)

1. HIV-1 protease
2. Gag-Pol polyprotein
3. Protease

ALIPDLAMETWLLLAVSLVLLYLYGTHSHGLFKKLGIPGPTPLPFLGNILSYHKGFCMFD
MECHKKYGKVWGFYDGQQPVLAITDPDMIKTVLVKECYSVFTNRRPFGPVGFMKSAISIA
EDEEWKRLRSLLSPTFTSGKLKEMVPIIAQYGDVLVRNLRREAETGKPVTLKDVFGAYSM
DVITSTSFGVNIDSLNNPQDPFVENTKKLLRFDFLDPFFLSITVFPFLIPILEVLNICVF
PREVTNFLRKSVKRMKESRLEDTQKHRVDFLQLMIDSQNSKETESHKALSDLELVAQSII
FIFAGYETTSSVLSFIMYELATHPDVQQKLQEEIDAVLPNKAPPTYDTVLQMEYLDMVVN
ETLRLFPIAMRLERVCKKDVEINGMFIPKGWVVMIPSYALHRDPKYWTEPEKFLPERFSK
KNKDNIDPYIYTPFGSGPRNCIGMRFALMNMKLALIRVLQNFSFKPCKETQIPLKLSLGG
LLQPEKPVVLKVESRDGTVSGA

1. Fragment

PQVTLWQRPIVTIKIGGQLKEALLDTGADDTVLEEMSLPGKWKPKMIGGIGGFIKVRQYD
QVSIEICGHKAIGTVLIGPTPVNIIGRNLLTQLGCTLNF

• RVP (PF00077 )

• None

• None

• Cytoplasmic

CCTCAGGTCACTCTTTGGCAACGACCCATAGTCACAATAAAGATAGGGGGGCAACTAAAG
GAAGCTCTATTAGATACAGGAGCAGATGATACAGTATTAGAAGAAATGAGTTTGCCAGGA
AAATGGAAACCAAAAATGATAGGGGGAATTGGAGGTTTTATCAAAGTAAGACAGTATGAT
CAGGTATCCATAGAAATCTGCGGACATAAAGCTATAGGTACAGTATTAATAGGACCTACA
CCTGTCAACATAATTGGAAGGAATCTGTTGACTCAGCTTGGCTGCACTTTAAATTTT

1. Servais J, Lambert C, Fontaine E, Plesseria JM, Robert I, Arendt V, Staub T, Schneider F, Hemmer R, Burtonboy G, Schmit JC: Comparison of DNA sequencing and a line probe assay for detection of human immunodeficiency virus type 1 drug resistance mutations in patients failing highly active antiretroviral therapy. J Clin Microbiol. 2001 Feb;39(2):454-9. [PubMed ]
2. Servais J, Lambert C, Fontaine E, Plesseria JM, Robert I, Arendt V, Staub T, Schneider F, Hemmer R, Burtonboy G, Schmit JC: Variant human immunodeficiency virus type 1 proteases and response to combination therapy including a protease inhibitor. Antimicrob Agents Chemother. 2001 Mar;45(3):893-900. [PubMed ]

1. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed ]
2. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed ]
3. Reddy GS, Ali A, Nalam MN, Anjum SG, Cao H, Nathans RS, Schiffer CA, Rana TM: Design and synthesis of HIV-1 protease inhibitors incorporating oxazolidinones as P2/P2' ligands in pseudosymmetric dipeptide isosteres. J Med Chem. 2007 Sep 6;50(18):4316-28. Epub 2007 Aug 16. [PubMed ]
4. Wittayanarakul K, Hannongbua S, Feig M: Accurate prediction of protonation state as a prerequisite for reliable MM-PB(GB)SA binding free energy calculations of HIV-1 protease inhibitors. J Comput Chem. 2007 Sep 11;. [PubMed ]
5. Garriga C, Perez-Elias MJ, Delgado R, Ruiz L, Najera R, Pumarola T, Alonso-Socas Mdel M, Garcia-Bujalance S, Menendez-Arias L: Mutational patterns and correlated amino acid substitutions in the HIV-1 protease after virological failure to nelfinavir- and lopinavir/ritonavir-based treatments. J Med Virol. 2007 Nov;79(11):1617-28. [PubMed ]

1. CA
2. Capsid protein p24
3. EC 2.7.7.49
4. EC 2.7.7.7
5. EC 3.1.26.4
6. EC 3.4.23.16
7. IN]
8. Integrase
9. MA
10. NC
11. Nucleocapsid protein p7
12. PR
13. Pr160Gag-Pol[Contains: Matrix protein p17
14. Protease
15. Retropepsin
16. Reverse transcriptase/ribonuclease H
17. Spacer peptide p2
18. TF
19. Transframe peptide
20. p15
21. p51 RT
22. p6*
23. p6-pol
24. p66 RT

MGARASVLSGGELDRWEKIRLRPGGKKKYKLKHIVWASRELERFAVNPGLLETSEGCRQI
LGQLQPSLQTGSEELRSLYNTVATLYCVHQRIEIKDTKEALDKIEEEQNKSKKKAQQAAA
DTGHSSQVSQNYPIVQNIQGQMVHQAISPRTLNAWVKVVEEKAFSPEVIPMFSALSEGAT
PQDLNTMLNTVGGHQAAMQMLKETINEEAAEWDRVHPVHAGPIAPGQMREPRGSDIAGTT
STLQEQIGWMTNNPPIPVGEIYKRWIILGLNKIVRMYSPTSILDIRQGPKEPFRDYVDRF
YKTLRAEQASQEVKNWMTETLLVQNANPDCKTILKALGPAATLEEMMTACQGVGGPGHKA
RVLAEAMSQVTNTATIMMQRGNFRNQRKMVKCFNCGKEGHTARNCRAPRKKGCWKCGKEG
HQMKDCTERQANFLREDLAFLQGKAREFSSEQTRANSPTISSEQTRANSPTRRELQVWGR
DNNSPSEAGADRQGTVSFNFPQITLWQRPLVTIKIGGQLKEALLDTGADDTVLEEMSLPG
RWKPKMIGGIGGFIKVRQYDQILIEICGHKAIGTVLVGPTPVNIIGRNLLTQIGCTLNFP
ISPIETVPVKLKPGMDGPKVKQWPLTEEKIKALVEICTEMEKEGKISKIGPENPYNTPVF
AIKKKDSTKWRKLVDFRELNKRTQDFWEVQLGIPHPAGLKKKKSVTVLDVGDAYFSVPLD
EDFRKYTAFTIPSINNETPGIRYQYNVLPQGWKGSPAIFQSSMTKILEPFKKQNPDIVIY
QYMDDLYVGSDLEIGQHRTKIEELRQHLLRWGLTTPDKKHQKEPPFLWMGYELHPDKWTV
QPIVLPEKDSWTVNDIQKLVGKLNWASQIYPGIKVRQLCKLLRGTKALTEVIPLTEEAEL
ELAENREILKEPVHGVYYDPSKDLIAEIQKQGQGQWTYQIYQEPFKNLKTGKYARMRGAH
TNDVKQLTEAVQKITTESIVIWGKTPKFKLPIQKETWETWWTEYWQATWIPEWEFVNTPP
LVKLWYQLEKEPIVGAETFYVDGAANRETKLGKAGYVTNKGRQKVVPLTNTTNQKTELQA
IYLALQDSGLEVNIVTDSQYALGIIQAQPDKSESELVNQIIEQLIKKEKVYLAWVPAHKG
IGGNEQVDKLVSAGIRKILFLDGIDKAQDEHEKYHSNWRAMASDFNLPPVVAKEIVASCD
KCQLKGEAMHGQVDCSPGIWQLDCTHLEGKVILVAVHVASGYIEAEVIPAETGQETAYFL
LKLAGRWPVKTIHTDNGSNFTSATVKAACWWAGIKQEFGIPYNPQSQGVVESMNKELKKI
IGQVRDQAEHLKTAVQMAVFIHNFKRKGGIGGYSAGERIVDIIATDIQTKELQKQITKIQ
NFRVYYRDSRNPLWKGPAKLLWKGEGAVVIQDNSDIKVVPRRKAKIIRDYGKQMAGDDCV
ASRQDED

• Specific for a P1 residue that is hydrophobic, and P1' variable, but often Pro

• RnaseH (PF00075 )
• RVP (PF00077 )
• RVT_1 (PF00078 )
• zf-CCHC (PF00098 )
• Gag_p17 (PF00540 )
• Integrase (PF00552 )
• Gag_p24 (PF00607 )
• rve (PF00665 )
• Integrase_Zn (PF02022 )
• RVT_connect (PF06815 )
• RVT_thumb (PF06817 )

• None

• None

• Nucleus. Cytoplasm (By similarity). Note=Following virus entry, the nuclear localization signal (NLS

ATGGGTGCGAGAGCGTCAGTATTAAGCGGGGGAGAATTAGATCGATGGGAAAAAATTCGG
TTAAGGCCAGGGGGAAAGAAAAAATATAAATTAAAACATATAGTATGGGCAAGCAGGGAG
CTAGAACGATTCGCAGTTAATCCTGGCCTGTTAGAAACATCAGAAGGCTGTAGACAAATA
CTGGGACAGCTACAACCATCCCTTCAGACAGGATCAGAAGAACTTAGATCATTATATAAT
ACAGTAGCAACCCTCTATTGTGTGCATCAAAGGATAGAGATAAAAGACACCAAGGAAGCT
TTAGACAAGATAGAGGAAGAGCAAAACAAAAGTAAGAAAAAAGCACAGCAAGCAGCAGCT
GACACAGGACACAGCAGTCAGGTCAGCCAAAATTACCCTATAGTGCAGAACATCCAGGGG
CAAATGGTACATCAGGCCATATCACCTAGAACTTTAAATGCATGGGTAAAAGTAGTAGAA
GAGAAGGCTTTCAGCCCAGAAGTAATACCCATGTTTTCAGCATTATCAGAAGGAGCCACC
CCACAAGATTTAAACACCATGCTAAACACAGTGGGGGGACATCAAGCAGCCATGCAAATG
TTAAAAGAGACCATCAATGAGGAAGCTGCAGAATGGGATAGAGTACATCCAGTGCATGCA
GGGCCTATTGCACCAGGCCAGATGAGAGAACCAAGGGGAAGTGACATAGCAGGAACTACT
AGTACCCTTCAGGAACAAATAGGATGGATGACAAATAATCCACCTATCCCAGTAGGAGAA
ATTTATAAAAGATGGATAATCCTGGGATTAAATAAAATAGTAAGAATGTATAGCCCTACC
AGCATTCTGGACATAAGACAAGGACCAAAAGAACCTTTTAGAGACTATGTAGACCGGTTC
TATAAAACTCTAAGAGCCGAGCAAGCTTCACAGGAGGTAAAAAATTGGATGACAGAAACC
TTGTTGGTCCAAAATGCGAACCCAGATTGTAAGACTATTTTAAAAGCATTGGGACCAGCG
GCTACACTAGAAGAAATGATGACAGCATGTCAGGGAGTAGGAGGACCCGGCCATAAGGCA
AGAGTTTTGGCTGAAGCAATGAGCCAAGTAACAAATACAGCTACCATAATGATGCAGAGA
GGCAATTTTAGGAACCAAAGAAAGATGGTTAAGTGTTTCAATTGTGGCAAAGAAGGGCAC
ACAGCCAGAAATTGCAGGGCCCCTAGGAAAAAGGGCTGTTGGAAATGTGGAAAGGAAGGA
CACCAAATGAAAGATTGTACTGAGAGACAGGCTAATTTTTTAGGGAAGATCTGGCCTTCC
TACAAGGGAAGGCCAGGGAATTTTCTTCAGAGCAGACCAGAGCCAACAGCCCCACCATTT
CTTCAGAGCAGACCAGAGCCAACAGCCCCACCAGAAGAGAGCTTCAGGTCTGGGGTAGAG
ACAACAACTCCCCCTCAGAAGCAGGAGCCGATAGACAAGGAACTGTATCCTTTAACTTCC
CTCAGATCACTCTTTGGCAACGACCCCTCGTCACAATAA

1. Sarafianos SG, Das K, Clark AD Jr, Ding J, Boyer PL, Hughes SH, Arnold E: Lamivudine (3TC) resistance in HIV-1 reverse transcriptase involves steric hindrance with beta-branched amino acids. Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):10027-32. [PubMed ]
2. Sluis-Cremer N, Arion D, Kaushik N, Lim H, Parniak MA: Mutational analysis of Lys65 of HIV-1 reverse transcriptase. Biochem J. 2000 May 15;348 Pt 1:77-82. [PubMed ]
3. Sarafianos SG, Clark AD Jr, Das K, Tuske S, Birktoft JJ, Ilankumaran P, Ramesha AR, Sayer JM, Jerina DM, Boyer PL, Hughes SH, Arnold E: Structures of HIV-1 reverse transcriptase with pre- and post-translocation AZTMP-terminated DNA. EMBO J. 2002 Dec 2;21(23):6614-24. [PubMed ]
4. Tachedjian G, Aronson HE, de los Santos M, Seehra J, McCoy JM, Goff SP: Role of residues in the tryptophan repeat motif for HIV-1 reverse transcriptase dimerization. J Mol Biol. 2003 Feb 14;326(2):381-96. [PubMed ]
5. Koval'skii DB, Kanibolotskii DS, Dubina VN, Korneliuk AI: [Conformational changes in HIV-1 proteinase: effect of protonation of the active center on conformation of HIV-1 proteinase in water] Ukr Biokhim Zh. 2002 Nov-Dec;74(6):135-8. [PubMed ]
6. Kohlstaedt LA, Wang J, Friedman JM, Rice PA, Steitz TA: Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science. 1992 Jun 26;256(5065):1783-90. [PubMed ]
7. Davies JF 2nd, Hostomska Z, Hostomsky Z, Jordan SR, Matthews DA: Crystal structure of the ribonuclease H domain of HIV-1 reverse transcriptase. Science. 1991 Apr 5;252(5002):88-95. [PubMed ]
8. Wohrl BM, Volkmann S, Moelling K: Mutations of a conserved residue within HIV-1 ribonuclease H affect its exo- and endonuclease activities. J Mol Biol. 1991 Aug 5;220(3):801-18. [PubMed ]
9. Jupp RA, Phylip LH, Mills JS, Le Grice SF, Kay J: Mutating P2 and P1 residues at cleavage junctions in the HIV-1 pol polyprotein. Effects on hydrolysis by HIV-1 proteinase. FEBS Lett. 1991 Jun 3;283(2):180-4. [PubMed ]
10. Erickson J, Neidhart DJ, VanDrie J, Kempf DJ, Wang XC, Norbeck DW, Plattner JJ, Rittenhouse JW, Turon M, Wideburg N, et al.: Design, activity, and 2.8 A crystal structure of a C2 symmetric inhibitor complexed to HIV-1 protease. Science. 1990 Aug 3;249(4968):527-33. [PubMed ]
11. 2476069 Mizrahi V, Lazarus GM, Miles LM, Meyers CA, Debouck C: Recombinant HIV-1 reverse transcriptase: purification, primary structure, and polymerase/ribonuclease H activities. Arch Biochem Biophys. 1989 Sep;273(2):347-58.
12. 2537531 Weber IT, Miller M, Jaskolski M, Leis J, Skalka AM, Wlodawer A: Molecular modeling of the HIV-1 protease and its substrate binding site. Science. 1989 Feb 17;243(4893):928-31.
13. 2578615 Ratner L, Haseltine W, Patarca R, Livak KJ, Starcich B, Josephs SF, Doran ER, Rafalski JA, Whitehorn EA, Baumeister K, et al.: Complete nucleotide sequence of the AIDS virus, HTLV-III. Nature. 1985 Jan 24-30;313(6000):277-84.
14. 2982104 Muesing MA, Smith DH, Cabradilla CD, Benton CV, Lasky LA, Capon DJ: Nucleic acid structure and expression of the human AIDS/lymphadenopathy retrovirus. Nature. 1985 Feb 7-13;313(6002):450-8.
15. 7532306 Rodgers DW, Gamblin SJ, Harris BA, Ray S, Culp JS, Hellmig B, Woolf DJ, Debouck C, Harrison SC: The structure of unliganded reverse transcriptase from the human immunodeficiency virus type 1. Proc Natl Acad Sci U S A. 1995 Feb 14;92(4):1222-6.
16. 7542140 Ding J, Das K, Tantillo C, Zhang W, Clark AD Jr, Jessen S, Lu X, Hsiou Y, Jacobo-Molina A, Andries K, et al.: Structure of HIV-1 reverse transcriptase in a complex with the non-nucleoside inhibitor alpha-APA R 95845 at 2.8 A resolution. Structure. 1995 Apr 15;3(4):365-79.
17. 7545077 Ding J, Das K, Moereels H, Koymans L, Andries K, Janssen PA, Hughes SH, Arnold E: Structure of HIV-1 RT/TIBO R 86183 complex reveals similarity in the binding of diverse nonnucleoside inhibitors. Nat Struct Biol. 1995 May;2(5):407-15.
18. 7552753 Eijkelenboom AP, Lutzke RA, Boelens R, Plasterk RH, Kaptein R, Hard K: The DNA-binding domain of HIV-1 integrase has an SH3-like fold. Nat Struct Biol. 1995 Sep;2(9):807-10.
19. 7613867 Priestle JP, Fassler A, Rosel J, Tintelnot-Blomley M, Strop P, Grutter MG: Comparative analysis of the X-ray structures of HIV-1 and HIV-2 proteases in complex with CGP 53820, a novel pseudosymmetric inhibitor. Structure. 1995 Apr 15;3(4):381-9.
20. 7687065 Jacobo-Molina A, Ding J, Nanni RG, Clark AD Jr, Lu X, Tantillo C, Williams RL, Kamer G, Ferris AL, Clark P, et al.: Crystal structure of human immunodeficiency virus type 1 reverse transcriptase complexed with double-stranded DNA at 3.0 A resolution shows bent DNA. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6320-4.
21. 8805568 Hsiou Y, Ding J, Das K, Clark AD Jr, Hughes SH, Arnold E: Structure of unliganded HIV-1 reverse transcriptase at 2.7 A resolution: implications of conformational changes for polymerization and inhibition mechanisms. Structure. 1996 Jul 15;4(7):853-60.
22. 9111014 Palaniappan C, Wisniewski M, Jacques PS, Le Grice SF, Fay PJ, Bambara RA: Mutations within the primer grip region of HIV-1 reverse transcriptase result in loss of RNase H function. J Biol Chem. 1997 Apr 25;272(17):11157-64.
23. 9450540 Hong L, Zhang XJ, Foundling S, Hartsuck JA, Tang J: Structure of a G48H mutant of HIV-1 protease explains how glycine-48 replacements produce mutants resistant to inhibitor drugs. FEBS Lett. 1997 Dec 22;420(1):11-6.
24. 9533880 Gao HQ, Boyer PL, Arnold E, Hughes SH: Effects of mutations in the polymerase domain on the polymerase, RNase H and strand transfer activities of human immunodeficiency virus type 1 reverse transcriptase. J Mol Biol. 1998 Apr 3;277(3):559-72.
25. 9813120 Hsiou Y, Das K, Ding J, Clark AD Jr, Kleim JP, Rosner M, Winkler I, Riess G, Hughes SH, Arnold E: Structures of Tyr188Leu mutant and wild-type HIV-1 reverse transcriptase complexed with the non-nucleoside inhibitor HBY 097: inhibitor flexibility is a useful design feature for reducing drug resistance. J Mol Biol. 1998 Nov 27;284(2):313-23.
26. 9831551 Huang H, Chopra R, Verdine GL, Harrison SC: Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance. Science. 1998 Nov 27;282(5394):1669-75.
27. 9878383 Turner BG, Summers MF: Structural biology of HIV. J Mol Biol. 1999 Jan 8;285(1):1-32.

PQITLWQRPIVTIKIGGQLKEALLDTGADDTVLEEMNLPGRWKPKLIGGIGGFVKVRQYD
QVPIEICGHKVIGTVLVGPTPANIIGRNLMTQIGCTLNF

• RVP (PF00077 )

• None

• None

• Cytoplasmic

CCTCAAATCACTCTTTGGCAACGACCCATCGTCACAATAAAGATAGGGGGGCAACTAAAG
GAAGCTCTATTAGATACAGGAGCAGATGATACAGTATTAGAAGAAATGAATTTGCCAGGA
AGATGGAAACCAAAATTGATAGGGGGAATTGGAGGTTTTGTCAAAGTAAGACAGTATGAT
CAGGTACCCATAGAAATCTGTGGACATAAGGTTATAGGTACAGTATTAGTAGGACCTACA
CCTGCCAACATAATTGGAAGGAATCTGATGACTCAGATTGGTTGCACTTTAAATTTT

1. Zolopa AR, Shafer RW, Warford A, Montoya JG, Hsu P, Katzenstein D, Merigan TC, Efron B: HIV-1 genotypic resistance patterns predict response to saquinavir-ritonavir therapy in patients in whom previous protease inhibitor therapy had failed. Ann Intern Med. 1999 Dec 7;131(11):813-21. [PubMed ]