In vivo antiviral activity of novel human immunodeficiency virus type 1 nucleocapsid p7 zinc finger inhibitors in a transgenic murine model

被引:33
作者
Schito, ML [1 ]
Goel, A
Song, Y
Inman, JK
Fattah, RJ
Rice, WG
Turpin, JA
Sher, A
Appella, E
机构
[1] NCI, Chem Immunol Sect, Cell Biol Lab, NIH, Bethesda, MD 20892 USA
[2] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA
[3] Achillon Pharmaceut, New Haven, CT 06510 USA
[4] NIAID, Bioorgan Chem Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA
[5] So Res Inst, Infect Dis Res Dept, Frederick, MD 21701 USA
关键词
D O I
10.1089/088922203762688595
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Control of human immunodeficiency virus through the use of inexpensive chemotherapeutics, with minimal side effects and decreased potential for engendering resistant virus, is a long-term therapeutic goal. In principle, this goal can be accomplished if viral replication in reservoirs of chronically and latently infected cells is addressed. As a first step, we have developed novel antiviral compounds based on a 2-mercaptobenzamide thioester chemotype, including the pyridinioalkanoyl thioesters, which specifically target the zinc fingers of the human immunodeficiency virus nucleocapsid protein (NCp7). Using these compounds in a murine transgenic model, in which infectious human immunodeficiency virus is induced from an integrated provirus, we show inhibition of transgenic spleen cell p24 expression with potencies comparable to acute infection assays using human peripheral blood lymphocytes. More importantly, transgenic mice treated in vivo with two 2-mercaptobenzamide thioesters expressed significantly lower plasma p24, and splenocytes from these animals produced fewer infectious virions. Thus, these thioesters may provide an effective means for inhibiting the expression of human immunodeficiency virus from integrated viral reservoirs.
引用
收藏
页码:91 / 101
页数:11
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