公开(公告)号：WO2006026524A3

公开(公告)日：2006-06-08

申请号：PCT/US2005030590

申请日：2005-08-26

Applicant: UNIV SOUTHERN METHODIST ,  HARROD ROBERT

Inventor： HARROD ROBERT

IPC: A01N43/04 ,  A61K31/70

CPC classification number: C12N9/90 ,  A61K31/522 ,  A61K31/551 ,  A61K38/52 ,  A61K48/00 ,  C07K14/005 ,  C12N2510/04 ,  C12N2740/16322 ,  C12Q1/6897 ,  C12Q1/703 ,  G01N33/5008 ,  G01N2333/163 ,  G01N2333/91245 ,  G01N2333/99 ,  C12Q2521/531

Abstract: Werner's Syndrome helicase (WRN) interacts in Tat/TAR-RNA chromatin-remodeling complexes assembled on the HIV-1 LTR to promote transcriptional activation and viral replication. WRN markedly increases basal HIV-1 transcription and synergizes with Tat to support LTR trans-activation. Inhibition of WRN functions, through expression of the trans-dominant-negative WRNK577M mutant, potently represses HIV-1 LTR trans-activation and prevents intracellular synthesis of p24Gag and inhibits virus production in HIV-infected H9HIV-1IIIB lymphocytes. Therefore, the present disclosure provides a novel target for anti-HIV therapy. Methods and compositions of the disclosure may be used to perform high throughput screens for small molecule anti-HIV therapeutics. Such therapeutics may inhibit a stage in the HIV replicative cycle not affected by current anti-HIV drugs.

Abstract translation: Werner综合征解旋酶（WRN）在HIV-1 LTR上组装的Tat / TAR-RNA染色质重塑复合物中相互作用以促进转录激活和病毒复制。 WRN显着增加基础HIV-1转录并与Tat协同支持LTR反式激活。 通过表达转显性失活WRNK577M突变体，WRN功能的抑制有效地抑制HIV-1 LTR反式激活并阻止细胞内合成p24Gag并抑制HIV感染的H9HIV-1IIIB淋巴细胞中的病毒产生。 因此，本公开提供了抗HIV治疗的新靶点。 本公开的方法和组合物可用于进行小分子抗HIV治疗剂的高通量筛选。 这种治疗剂可以抑制HIV复制周期中不受当前抗HIV药物影响的阶段。

公开(公告)号：WO2006026524A2

公开(公告)日：2006-03-09

申请号：PCT/US2005/030590

申请日：2005-08-26

Applicant: SOUTHERN METHODIST UNIVERSITY ,  HARROD, Robert

Inventor： HARROD, Robert

IPC: A61K48/00 ,  A61K38/16 ,  A61K31/551

CPC classification number: C12N9/90 ,  A61K31/522 ,  A61K31/551 ,  A61K38/52 ,  A61K48/00 ,  C07K14/005 ,  C12N2510/04 ,  C12N2740/16322 ,  C12Q1/6897 ,  C12Q1/703 ,  G01N33/5008 ,  G01N2333/163 ,  G01N2333/91245 ,  G01N2333/99 ,  C12Q2521/531

Abstract: Werner's Syndrome helicase (WRN) interacts in Tat/TAR-RNA chromatin-remodeling complexes assembled on the HIV-1 LTR to promote transcriptional activation and viral replication. WRN markedly increases basal HIV-1 transcription and synergizes with Tat to support LTR trans-activation. Inhibition of WRN functions, through expression of the trans-dominant-negative WRNK577M mutant, potently represses HIV-1 LTR trans-activation and prevents intracellular synthesis of p24Gag and inhibits virus production in HIV-infected H9HIV-1IIIB lymphocytes. Therefore, the present disclosure provides a novel target for anti-HIV therapy. Methods and compositions of the disclosure may be used to perform high throughput screens for small molecule anti-HIV therapeutics. Such therapeutics may inhibit a stage in the HIV replicative cycle not affected by current anti-HIV drugs.

Abstract translation: 维纳综合征解旋酶（WRN）与组装在HIV-1 LTR上的Tat / TAR-RNA染色质重塑复合物相互作用，以促进转录激活和病毒复制。 WRN显着增加基本的HIV-1转录，并与Tat协同作用以支持LTR反式激活。 通过反式显性阴性WRNK577M突变体的表达抑制WRN功能有效抑制HIV-1 LTR反式激活，并阻止p24Gag的细胞内合成并抑制HIV感染的H9HIV-1IIIB淋巴细胞中的病毒产生。 因此，本公开提供了抗HIV治疗的新靶标。 本公开的方法和组合物可用于对小分子抗HIV治疗剂进行高通量筛选。 这种治疗剂可能会抑制HIV复制循环中不受现有抗HIV药物影响的阶段。