Kuritzkes Daniel R
Section of Retroviral Therapeutics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02139, USA.
Curr Opin HIV AIDS. 2009 Mar;4(2):82-7. doi: 10.1097/COH.0b013e328322402e.
To provide an overview of HIV-1 entry inhibitors, with a focus on chemokine receptor antagonists.
Entry of HIV-1 into target cells is an ordered multistep process involving attachment, co-receptor binding, and fusion. Inhibitors of each step have been identified and shown to have antiviral activity in clinical trials. Phase 1-2 trials of monoclonal antibodies and small-molecule attachment inhibitors have demonstrated activity in HIV-1-infected patients, but none has progressed to later-phase clinical trials. The postattachment inhibitor ibalizumab has shown activity in phase 1 and 2 trials; further studies are anticipated. The CCR5 antagonists maraviroc (now been approved for clinical use) and vicriviroc (in phase 3 trials) have shown significant benefit in controlled trials in treatment-experienced patients; additional CCR5 antagonists are in various stages of clinical development. Targeting CXCR4 has proven to be more challenging. Although proof of concept has been demonstrated in phase 1-2 trials of two compounds, neither proved suitable for chronic administration. Little progress has been reported in developing longer acting or orally bioavailable fusion inhibitors.
A CCR5 antagonist and a fusion inhibitor are approved for use as HIV-1 entry inhibitors. Development of drugs targeting other steps in HIV-1 entry is ongoing.
概述HIV-1进入抑制剂，重点关注趋化因子受体拮抗剂。
HIV-1进入靶细胞是一个有序的多步骤过程，涉及附着、共受体结合和融合。已鉴定出每个步骤的抑制剂，并在临床试验中显示出抗病毒活性。单克隆抗体和小分子附着抑制剂的1-2期试验已在HIV-1感染患者中证明有活性，但均未进入后期临床试验。附着后抑制剂ibalizumab在1期和2期试验中已显示出活性；预计将进行进一步研究。CCR5拮抗剂马拉维若（现已批准用于临床）和维立瑞韦（处于3期试验）在有治疗经验患者的对照试验中已显示出显著疗效；其他CCR5拮抗剂正处于临床开发的不同阶段。事实证明，靶向CXCR4更具挑战性。尽管在两种化合物的1-2期试验中已证明有概念验证，但两者均不适合长期给药。在开发长效或口服生物利用度高的融合抑制剂方面进展甚微。
一种CCR5拮抗剂和一种融合抑制剂已被批准用作HIV-1进入抑制剂。针对HIV-1进入其他步骤的药物研发正在进行中。
