Designed Multiple Ligands: An Emerging Anti-HIV Drug Discovery Paradigm

被引:75
作者
Zhan, Peng [1 ]
Liu, Xinyong [1 ]
机构
[1] Shandong Univ, Sch Pharmaceut Sci, Dept Med Chem, Jinan 250012, Shandong, Peoples R China
基金
中国国家自然科学基金; 高等学校博士学科点专项科研基金;
关键词
Anti-HIV; designed multiple ligands; drug design; pharmacophore; bifunctional drugs; combination therapy; double-drug; HUMAN-IMMUNODEFICIENCY-VIRUS; POTENTIAL MULTIFUNCTIONAL INHIBITORS; REVERSE-TRANSCRIPTASE INHIBITOR; CYCLOSPORINE-A ANALOG; INTEGRASE INHIBITORS; PROTEASE INHIBITORS; COSALANE ANALOGS; DUAL INHIBITORS; RIBONUCLEASE-H; BETULINIC ACID;
D O I
10.2174/138161209788453266
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Currently, the effect of AIDS single-target chemotherapy is severely compromised by the quick emergence of resistant HIV strains. Highly active antiretroviral therapy (HAART) combines HIV reverse transcriptase inhibitors with protease inhibitors or integrase inhibitors, and successfully suppresses HIV viral load to an undetectable level, dramatically improving the life quality of AIDS patients. However, the benefits of this approach are often compromised by poor patient compliance. Recently, there has been a move toward multicomponent drugs whereby two or more agents are coformulated in a single tablet to make dosing regimes simpler and thereby to improve patient compliance, but there are significant risks involved in the development of multicomponent drugs. Designed multiple ligands (DMLs) therapy as an emerging anti-HIV drug discovery paradigm, using a single entity to inhibit multitargets could yield improved patient compliance, thus reducing the likelihood of drug resistance. The exploration of such multifunctional ligands has proven valuable for anti-HIV leads discovery. However, presently many multifunctional scaffolds were first discovered by serendipity or screening; rational design by combining existing monofunctional scaffolds remains an enormous challenge. A key issue in the design of multiple ligands is attaining a balanced activity at each target of interest while simultaneously achieving a wider selectivity and a suitable pharmacokinetic profile. This review of literature examples introduce numerous attractive lead compounds, capable of interfering with different stages of HIV infection and AIDS pathogenesis, which reveals trends and insights that might provide valuable clues for novel anti-HIV drug design and help medicinal chemists discover the next generation of multiple ligands.
引用
收藏
页码:1893 / 1917
页数:25
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