McDonnell N B, De Guzman R N, Rice W G, Turpin J A, Summers M F
Howard Hughes Medical Institute, University of Maryland Baltimore County 21228, USA.
J Med Chem. 1997 Jun 20;40(13):1969-76. doi: 10.1021/jm970147+.
The highly conserved and mutationally intolerant retroviral zinc finger motif of the HIV-1 nucleocapsid protein (NC) is an attractive target for drug therapy due to its participation in multiple stages of the viral replication cycle. A literature search identified cystamine, thiamine disulfide, and disulfiram as compounds that have been shown to inhibit HIV-1 replication by poorly defined mechanisms and that have electrophilic functional groups that might react with the metal-coordinating sulfur atoms of the retroviral zinc fingers and cause zinc ejection. 1H NMR studies reveal that these compounds readily eject zinc from synthetic peptides with sequences corresponding to the HIV-1 NC zinc fingers, as well as from the intact HIV-1 NC protein. In contrast, the reduced forms of disulfiram and cystamine, diethyl dithiocarbamate and cysteamine, respectively, were found to be ineffective at zinc ejection, although cysteamine formed a transient complex with the zinc fingers. Studies with HIV-1-infected human T-cells and monocyte/macrophage cultures revealed that cystamine and cysteamine possess significant antiviral properties at nontoxic concentrations, which warrant their consideration as therapeutically useful anti-HIV agents.
由于HIV-1核衣壳蛋白（NC）高度保守且对突变不耐受的逆转录病毒锌指基序参与病毒复制周期的多个阶段，因此它是药物治疗的一个有吸引力的靶点。文献检索发现胱胺、硫胺二硫化物和双硫仑是已被证明可通过尚不明确的机制抑制HIV-1复制的化合物，并且它们具有亲电官能团，可能与逆转录病毒锌指的金属配位硫原子发生反应并导致锌离子释放。1H NMR研究表明，这些化合物能轻易地从与HIV-1 NC锌指序列相对应的合成肽以及完整的HIV-1 NC蛋白中释放锌离子。相比之下，双硫仑和胱胺的还原形式，即二乙基二硫代氨基甲酸盐和半胱胺，虽然半胱胺与锌指形成了瞬时复合物，但发现它们在锌离子释放方面无效。对感染HIV-1的人类T细胞和单核细胞/巨噬细胞培养物的研究表明，胱胺和半胱胺在无毒浓度下具有显著的抗病毒特性，这使得它们有理由被视为具有治疗用途的抗HIV药物。
