1eet: Difference between revisions
New page: left|200px<br /> <applet load="1eet" size="450" color="white" frame="true" align="right" spinBox="true" caption="1eet, resolution 2.73Å" /> '''HIV-1 REVERSE TRANS... |
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[[Image:1eet.gif|left|200px]]<br /> | [[Image:1eet.gif|left|200px]]<br /><applet load="1eet" size="350" color="white" frame="true" align="right" spinBox="true" | ||
<applet load="1eet" size=" | |||
caption="1eet, resolution 2.73Å" /> | caption="1eet, resolution 2.73Å" /> | ||
'''HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH THE INHIBITOR MSC204'''<br /> | '''HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH THE INHIBITOR MSC204'''<br /> | ||
==Overview== | ==Overview== | ||
The further development of allosteric HIV-1 RT inhibitors in the urea | The further development of allosteric HIV-1 RT inhibitors in the urea analogue series of PETT (phenylethylthiazolylthiourea) derivatives is described here. The series includes derivatives with an ethyl linker (1-5) and racemic (6-16) and enantiomeric (17-20) cis-cyclopropane compounds. The antiviral activity was determined both at the RT level and in cell culture on both wild-type and mutant forms of HIV-1. Most compounds have anti-HIV-1 activity on the wt in the nanomolar range. Resistant HIV-1 was selected in vitro for some of the compounds, and the time for resistant HIV-1 to develop was longer for urea-PETT compounds than it was for reference compounds. Preliminary pharmacokinetics in rats showed that compound 18 is orally bioavailable and penetrates well into the brain. The three-dimensional structure of complexes between HIV-1 RT and two enantiomeric compounds (17 and 18) have been determined. The structures show similar binding in the NNI binding pocket. The propionylphenyl moieties of both inhibitors show perfect stacking to tyrosine residues 181 and 188. The cyclopropyl moiety of the (+)-enantiomer 18 exhibits optimal packing distances for the interactions with leucine residue 100 and valine residue 179. | ||
==About this Structure== | ==About this Structure== | ||
1EET is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1] with BFU as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/RNA-directed_DNA_polymerase RNA-directed DNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.49 2.7.7.49] Full crystallographic information is available from [http:// | 1EET is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1] with <scene name='pdbligand=BFU:'>BFU</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/RNA-directed_DNA_polymerase RNA-directed DNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.49 2.7.7.49] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EET OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Fridborg, K.]] | [[Category: Fridborg, K.]] | ||
[[Category: Hogberg, M.]] | [[Category: Hogberg, M.]] | ||
[[Category: Johansson, N | [[Category: Johansson, N G.]] | ||
[[Category: Kangasmetsa, J.]] | [[Category: Kangasmetsa, J.]] | ||
[[Category: Lovgren, S.]] | [[Category: Lovgren, S.]] | ||
[[Category: Noreen, R.]] | [[Category: Noreen, R.]] | ||
[[Category: Oberg, B.]] | [[Category: Oberg, B.]] | ||
[[Category: Sahlberg, B | [[Category: Sahlberg, B L.]] | ||
[[Category: Sahlberg, C.]] | [[Category: Sahlberg, C.]] | ||
[[Category: Unge, T.]] | [[Category: Unge, T.]] | ||
| Line 33: | Line 32: | ||
[[Category: protein-inhibitor complex]] | [[Category: protein-inhibitor complex]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:26:58 2008'' | ||
Revision as of 13:27, 21 February 2008
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HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH THE INHIBITOR MSC204
OverviewOverview
The further development of allosteric HIV-1 RT inhibitors in the urea analogue series of PETT (phenylethylthiazolylthiourea) derivatives is described here. The series includes derivatives with an ethyl linker (1-5) and racemic (6-16) and enantiomeric (17-20) cis-cyclopropane compounds. The antiviral activity was determined both at the RT level and in cell culture on both wild-type and mutant forms of HIV-1. Most compounds have anti-HIV-1 activity on the wt in the nanomolar range. Resistant HIV-1 was selected in vitro for some of the compounds, and the time for resistant HIV-1 to develop was longer for urea-PETT compounds than it was for reference compounds. Preliminary pharmacokinetics in rats showed that compound 18 is orally bioavailable and penetrates well into the brain. The three-dimensional structure of complexes between HIV-1 RT and two enantiomeric compounds (17 and 18) have been determined. The structures show similar binding in the NNI binding pocket. The propionylphenyl moieties of both inhibitors show perfect stacking to tyrosine residues 181 and 188. The cyclopropyl moiety of the (+)-enantiomer 18 exhibits optimal packing distances for the interactions with leucine residue 100 and valine residue 179.
About this StructureAbout this Structure
1EET is a Protein complex structure of sequences from Human immunodeficiency virus 1 with as ligand. Active as RNA-directed DNA polymerase, with EC number 2.7.7.49 Full crystallographic information is available from OCA.
ReferenceReference
Urea-PETT compounds as a new class of HIV-1 reverse transcriptase inhibitors. 3. Synthesis and further structure-activity relationship studies of PETT analogues., Hogberg M, Sahlberg C, Engelhardt P, Noreen R, Kangasmetsa J, Johansson NG, Oberg B, Vrang L, Zhang H, Sahlberg BL, Unge T, Lovgren S, Fridborg K, Backbro K, J Med Chem. 1999 Oct 7;42(20):4150-60. PMID:10514285
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