The benzamide derivative N-[1-(7-tert-Butyl-1H-indol-3-ylmethyl)-2-(4-cyclopropanecarbonyl-3-methyl-piperazin-1-yl)-2-oxo-ethyl]-4-nitro-benzamide (SP-10) reduces HIV-1 infectivity in vitro by modifying actin dynamics.
Current treatments for patients infected with HIV are suboptimal. There is a need for new HIV therapies that act through different mechanisms than current treatments. We investigated the in vitro efficacy, safety and mechanism of action of the benzamide derivative N-[1-(7-tert-Butyl-1H-indol-3-ylmethyl)-2-(4-cyclopropanecarbonyl-3-methyl-piperazin-1-yl)-2-oxo-ethyl]-4-nitro-benzamide (SP-10), a potential new HIV treatment. When HIV-1-responsive engineered HeLa cells were pre-incubated for 48 h with either SP-10 or zidovudine (AZT), SP-10 was able to inhibit viral replication at much lower concentrations (IC50 = 0.036 nM) than AZT (IC50 = 27.4 nM). In contrast to AZT, SP-10 also inhibited replication of the multidrug-resistant HIV-1 strain MDR-769 in the HeLa cell model. In co-incubation experiments, SP-10 also inhibited the CCR5-sensitive HIV-1 BaL virus replication in human peripheral blood mononuclear cells. SP-10 displayed very low toxicity compared with current antiviral treatments. Confocal laser scanning microscopy and immunoprecipitation studies showed that SP-10 reduced the expression of CD4 and CCR5 on the surface of the host cell. SP-10 also reduced the level of gp120 binding to the cell surface. Confocal laser scanning microscopy studies showed that SP-10 blocked the formation of actin filaments (F-actin) and altered actin accumulation near the cell surface. These promising results suggest that SP-10 has a novel mechanism of action that enables effective inhibition of HIV-1 binding and cell entry. Further development of SP-10 as a new HIV treatment appears warranted.
Xu
Jing
J
Department of Biochemistry, Georgetown University Medical Center, Washington, DC, USA.
Lecanu
Laurent
L
Tan
Matthew
M
Yao
Wenguo
W
Greeson
Janet
J
Papadopoulos
Vassilios
V
D000199:Actins / Q000502:physiology*; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D001549:Benzamides / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D002478:Cells, Cultured; D024921:Drug Resistance, Multiple, Viral; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D011485:Protein Binding; D019713:Receptors, CCR5 / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000494:pharmacology
D000199:Actins; D019380:Anti-HIV Agents; D001549:Benzamides; D015699:HIV Envelope Protein gp120; C518541:N-(1-(7-tert-butyl-1H-indol-3-ylmethyl)-2-(4-cyclopropanecarbonyl-3-methyl-piperazin-1-yl)-2-oxoethyl)-4-nitrobenzamide; D019713:Receptors, CCR5; D015215:Zidovudine; C037689:benzamide