Microbicides based on hydrogel have become an effective way to prevent the HIV replication and transmission because of their convenience and prolonging drug release. In this study, a hybrid thermo-sensitive hydrogel constituted by nanosized layered double hydroxides and poloxamer 407 (P407) was constructed and co-loaded with both hydrophobic and hydrophilic drug. The LDH-P407 hydrogel could achieve sol-gel transition at body temperature. The in vivo experiment showed that LDH-P407 hydrogel can achieve controlled release of theaflavin and Nile red (hydrophobic drug model) into blood by vaginal drug delivery, meanwhile the hydrogel showed barely mucosal irritation. In addition, ex vivo experiment showed that the nifeviroc-loaded LDH-P407 hydrogel was able to specifically bind co-receptor CCR5 of DCs cells. Therefore, the LDH-P407 hydrogel would be a promising carrier for intravaginal delivery of anti-HIV drugs.

01 May 2012·Journal of Biological ChemistryQ2 · BIOLOGY

CCR5 Antagonist TD-0680 Uses a Novel Mechanism for Enhanced Potency against HIV-1 Entry, Cell-mediated Infection, and a Resistant Variant

Q2 · BIOLOGY

Article

Author: Sai Kam Li ; Li Liu ; Allen Ka Loon Cheung ; Haibo Wang ; Terrence Chi Kong Lau ; Zhiwei Chen ; Zhiwei Wu ; Bojian Zheng ; Zhiwu Tan ; Yuanxi Kang ; Ben Li ; Xiaofan Lu ; Li Chen ; Jianguo Liang ; Jenny Ng

Regardless of the route of transmission, R5-tropic HIV-1 predominates early in infection, rendering C-C chemokine receptor type 5 (CCR5) antagonists as attractive agents not only for antiretroviral therapy but also for prevention. Here, we report the specificity, potency, and underlying mechanism of action of a novel small molecule CCR5 antagonist, TD-0680. TD-0680 displayed the greatest potency against a diverse group of R5-tropic HIV-1 and SIV strains when compared with its prodrug, TD-0232, the Food and Drug Administration-approved CCR5 antagonist Maraviroc, and TAK-779, with EC(50) values in the subnanomolar range (0.09-2.29 nm). Importantly, TD-0680 was equally potent at blocking envelope-mediated cell-cell fusion and cell-mediated viral transmission as well as the replication of a TAK-779/Maraviroc-resistant HIV-1 variant. Interestingly, TD-0232 and TD-0680 functioned differently despite binding to a similar transmembrane pocket of CCR5. Site-directed mutagenesis, drug combination, and antibody blocking assays identified a novel mechanism of action of TD-0680. In addition to binding to the transmembrane pocket, the unique exo configuration of this molecule protrudes and sterically blocks access to the extracellular loop 2 (ECL2) region of CCR5, thereby interrupting the interaction between virus and its co-receptor more effectively. This mechanism of action was supported by the observations of similar TD-0680 potency against CD4-dependent and -independent SIV strains and by molecular docking analysis using a CCR5 model. TD-0680, therefore, merits development as an anti-HIV-1 agent for therapeutic purposes and/or as a topical microbicide for the prevention of sexual transmission of R5-tropic HIV-1.

01 Nov 2011·Journal of Pharmaceutical and Biomedical AnalysisQ3 · MEDICINE

Determination of nifeviroc, a novel CCR5 antagonist: Application to a pharmacokinetic study

Q3 · MEDICINE

Article

Author: Dong Xie ; Zeneng Cheng ; Wei Wu ; Zhi Liu ; Zhenkun Gu ; Peng Yu ; Liling Ran

Nifeviroc is a novel CCR5 antagonist used for the treatment of HIV type-1 infection. A LC-ESI-MS/MS method for the determination of nifeviroc in human plasma was developed and validated. The calibration curve (r(2)=0.9993) of nifeviroc was established at the range of 1.924-2935 μg L(-1). The intra- and inter-day precisions (RSD%) were all less than 7%, and the accuracies at three concentration levels were all within 100 ± 5%. This validated method was then successfully applied to a pharmacokinetic study in health Chinese volunteers.

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Indication	Highest Phase	Country/Location	Organization	Date
HIV Infections	Phase 1	CN	Avexa LLC	-
HIV Infections	Phase 1	CN	Shanghai Institutes for Biological Sciences CAS	-
HIV Infections	Phase 1	CN	Shanghai Targetdrug Co., Ltd.	-
HIV Infections	Phase 1	CN	Shanghai Institute of Organic Chemistry	-

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