小分子CCR5拮抗剂研究进展

趋化因子受体5(CCR5)是HIV-1侵入宿主细胞的主要辅助受体之一.目前已发现许多小分子CCR5拮抗剂,其中一些化合物已进入临床研究和应用.本文介绍了小分子CCR5拮抗剂的作用机制,综述了近几年来各种不同结构类型的小分子CCR5拮抗剂的研究进展.     

新型抗艾滋病药物——HIV进入抑制剂的研究进展

HIV与靶细胞融合的过程是药物干预的重要环节。融合过程主要由H IV包被蛋白表面亚基gp120和跨膜亚基gp41介导。H IV gp120与靶细胞上的CD4分子和辅助受体(趋化因子受体CCR5或CXCR4等)结合,导致gp41的构型发生改变,启动病毒包膜与靶细胞膜的融合。在融合过程中,病毒和靶细胞上的这些蛋白和受体均可作为药物的作用靶点,寻找抑制H IV进入靶细胞的药物用来治疗H IV感染和艾滋病。作用于gp41的肽类药物T-20已被美国FDA批准上市,表明继逆转录酶抑制剂和蛋白酶抑制剂后,H IV进入抑制剂作为第3类抗H IV药物开始在临床上应用。作为一种新机制的抗H IV药物,H IV进入抑制剂单独或与逆转录酶抑制剂和蛋白酶抑制剂联合应用,将有助于提高药物的疗效,降低毒副作用,并可望挽救对现有抗H IV药物耐药的艾滋病病人的生命。该文综述了近年来H IV进入抑制剂的研究进展。     

Small molecule HIV entry inhibitors: Part I. Chemokine receptor antagonists: 2004 - 2010

INTRODUCTION: HIV/AIDS is one of the most devastating diseases in the world affecting > 40 million people worldwide. Morbidity and mortality from AIDS are significantly reduced due to the advent of highly active antiretroviral therapy (HAART). Long-term toxicity, emergence of drug resistant HIV strains and drug-drug interactions limit the effectiveness of HAART therapy. Chemokine receptor antagonists can provide drugs with lesser side effects and enhanced anti-HIV activity. Maraviroc, a chemokine co-receptor 5 (CCR5) antagonist from Pfizer, is already in clinical use. AREAS COVERED: This review covers patents and patent applications for small molecule CCR5 and CXC chemokine receptor 4 (CXCR4) antagonists published between 2004 and 2010 and related literature with a focus on recent developments based on lead generation and lead modification. The reader will gain information about the development of small molecule CCR5 and CXCR4 antagonists from the major pharmaceutical and biopharmaceutical companies. EXPERT OPINION: Several small lead molecules (CCR5 and CXCR4 antagonists) have been modified over this period for enhanced therapeutic activity and to obtain drug-like properties. CCR5 antagonists such as TBK-652 and TBK-220 from Tobira Therapeutics, and vicriviroc from Schering Plough showed a lot of promise in the developmental stage.     

Inhibition of CCR5-mediated infection by diverse R5 and R5X4 HIV and SIV isolates using novel small molecule inhibitors of CCR5: effects of viral diversity, target cell and receptor density

Highly active anti-retroviral therapy (HAART) has been very effective in reducing viral loads in human immunodeficiency virus (HIV)-1 patients. However, current therapies carry detrimental side effects, require complex drug regimes and are threatened by the emergence of drug-resistant variants. There is an urgent need for new anti-HIV drugs that target different stages of the replication cycle. Several synthetic small organic molecules that inhibit HIV infection by binding to the CCR5 coreceptor without causing cell activation have already been reported. Here, we have exploited a series of CCR5 antagonists to investigate their effects on diverse HIV and the simian counterpart (SIV) isolates for infection of a variety of cell types via different concentrations of cell surface CCR5. These inhibitors show no cross-reactivity against alternative HIV coreceptors including CCR3, CCR8, GPR1, APJ, CXCR4 and CXCR6. They are able to inhibit a diverse range of R5 and R5X4 HIV-1 isolates as well as HIV-2 and SIV strains. Inhibition was observed in cell lines as well as primary PBMCs and macrophages. The extent of inhibition was dependent on cell type and on cell surface CCR5 concentration. Our results underscore the potential of CCR5 inhibitors for clinical development.     

HIV entry inhibitors:progress in development and application

This review discusses recent progress in the development of anti-HIV agents, with emphasis on small molecule HIV-1 entry inhibitors.  The entry inhibitors primarily target HIV-1 envelope glycoproteins or the cellular receptors, CD4 and chemokine receptors.  Two of the entry inhibitors, enfuvirtide and maraviroc, have been approved by the US FDA for AIDS therapy.  The drug resistance associated with some of the entry inhibitors will also be discussed.