2b6a: Difference between revisions

Revision as of 17:34, 21 February 2008

Crystal structure of HIV-1 reverse transcriptase (RT) in complex with THR-50

OverviewOverview

The development of new nonnucleoside inhibitors of human immunodeficiency virus type-1 (HIV-1) reverse transcriptase (RT) active against the drug-induced mutations in RT continues to be a very important goal of AIDS research. We used a known inhibitor of HIV-1 RT, 1-(2,6-difluorophenyl)-1H,3H-thiazolo[3,4-alpha]benzimidazole (TZB), as the lead structure for drug design with the objective of making more potent inhibitors against both wild-type (WT) and variant RTs. A series of structurally related 1,2-substituted benzimidazoles was synthesized and evaluated for their ability to inhibit in vitro polymerization by HIV-1 WT RT. A structure-activity study was carried out for the series of compounds to determine the optimum groups for substitution of the benzimidazole ring at the N1 and C2 positions. The best inhibitor, 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-methylbenzimida zole (35), has an IC50 = 200 nM against HIV-1 WT RT in an in vitro enzyme assay. Cytoprotection assays utilizing HIV-infected MT-4 cells revealed that 35 had strong antiviral activity (EC50 = 440 nM) against wild-type virus while retaining broad activity against many clinically observed HIV-1 strains resistant to nonnucleoside inhibitors. Overall, the activity of 35 against wild-type and resistant strains with amino acid substitution in RT is 4-fold or greater than that of TZB and is comparable to that of other nonnucleoside inhibitors currently undergoing clinical trials, most of which do not have the capacity to inhibit the variant forms of the enzyme.

About this StructureAbout this Structure

2B6A 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

Synthesis and biological activity of novel nonnucleoside inhibitors of HIV-1 reverse transcriptase. 2-Aryl-substituted benzimidazoles., Roth T, Morningstar ML, Boyer PL, Hughes SH, Buckheit RW Jr, Michejda CJ, J Med Chem. 1997 Dec 19;40(26):4199-207. PMID:9435891

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 ==Overview==
-The development of new nonnucleoside inhibitors of human immunodeficiency, virus type-1 (HIV-1) reverse transcriptase (RT) active against the, drug-induced mutations in RT continues to be a very important goal of AIDS, research. We used a known inhibitor of HIV-1 RT, 1-(2,6-difluorophenyl)-1H,3H-thiazolo[3,4-alpha]benzimidazole (TZB), as, the lead structure for drug design with the objective of making more, potent inhibitors against both wild-type (WT) and variant RTs. A series of, structurally related 1,2-substituted benzimidazoles was synthesized and, evaluated for their ability to inhibit in vitro polymerization by HIV-1 WT, RT. A structure-activity study was carried out for the series of compounds, to determine the optimum groups for substitution of the benzimidazole ring, at the N1 and C2 positions. The best inhibitor, 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-methylbenzimida zole (35), has an IC50 = 200 nM against HIV-1 WT RT in an in vitro enzyme assay., Cytoprotection assays utilizing HIV-infected MT-4 cells revealed that 35, had strong antiviral activity (EC50 = 440 nM) against wild-type virus, while retaining broad activity against many clinically observed HIV-1, strains resistant to nonnucleoside inhibitors. Overall, the activity of 35, against wild-type and resistant strains with amino acid substitution in RT, is 4-fold or greater than that of TZB and is comparable to that of other, nonnucleoside inhibitors currently undergoing clinical trials, most of, which do not have the capacity to inhibit the variant forms of the enzyme.
+The development of new nonnucleoside inhibitors of human immunodeficiency virus type-1 (HIV-1) reverse transcriptase (RT) active against the drug-induced mutations in RT continues to be a very important goal of AIDS research. We used a known inhibitor of HIV-1 RT, 1-(2,6-difluorophenyl)-1H,3H-thiazolo[3,4-alpha]benzimidazole (TZB), as the lead structure for drug design with the objective of making more potent inhibitors against both wild-type (WT) and variant RTs. A series of structurally related 1,2-substituted benzimidazoles was synthesized and evaluated for their ability to inhibit in vitro polymerization by HIV-1 WT RT. A structure-activity study was carried out for the series of compounds to determine the optimum groups for substitution of the benzimidazole ring at the N1 and C2 positions. The best inhibitor, 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-methylbenzimida zole (35), has an IC50 = 200 nM against HIV-1 WT RT in an in vitro enzyme assay. Cytoprotection assays utilizing HIV-infected MT-4 cells revealed that 35 had strong antiviral activity (EC50 = 440 nM) against wild-type virus while retaining broad activity against many clinically observed HIV-1 strains resistant to nonnucleoside inhibitors. Overall, the activity of 35 against wild-type and resistant strains with amino acid substitution in RT is 4-fold or greater than that of TZB and is comparable to that of other nonnucleoside inhibitors currently undergoing clinical trials, most of which do not have the capacity to inhibit the variant forms of the enzyme.
 ==About this Structure==
@@ Line 15: / Line 15: @@
 [[Category: RNA-directed DNA polymerase]]
 [[Category: Arnold, E.]]
-[[Category: Buckheit, R.W.]]
+[[Category: Buckheit, R W.]]
 [[Category: Das, K.]]
-[[Category: Michejda, C.J.]]
+[[Category: Michejda, C J.]]
-[[Category: Morningstar, M.L.]]
+[[Category: Morningstar, M L.]]
 [[Category: Roth, T.]]
-[[Category: Smith, M.K.]]
+[[Category: Smith, M K.]]
 [[Category: Watson, K.]]
 [[Category: Zajac, M.]]
@@ Line 32: / Line 32: @@
 [[Category: rt]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 17:15:30 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:34:37 2008''