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Gnidimacrin, a Potent Anti-HIV Diterpene, Can Eliminate Latent HIV-1 Ex Vivo by Activation of Protein Kinase C β.

Publication ,  Journal Article
Lai, W; Huang, L; Zhu, L; Ferrari, G; Chan, C; Li, W; Lee, K-H; Chen, C-H
Published in: J Med Chem
November 12, 2015

HIV-1-latency-reversing agents, such as histone deacetylase inhibitors (HDACIs), were ineffective in reducing latent HIV-1 reservoirs ex vivo using CD4 cells from patients as a model. This deficiency poses a challenge to current pharmacological approaches for HIV-1 eradication. The results of this study indicated that gnidimacrin (GM) was able to markedly reduce the latent HIV-1 DNA level and the frequency of latently infected cells in an ex vivo model using patients peripheral blood mononuclear cells. GM induced approximately 10-fold more HIV-1 production than the HDACI SAHA or romidepsin, which may be responsible for the effectiveness of GM in reducing latent HIV-1 levels. GM achieved these effects at low picomolar concentrations by selective activation of protein kinase C βI and βII. Notably, GM was able to reduce the frequency of HIV-1 latently infected cells at concentrations without global T cell activation or stimulating inflammatory cytokine production. GM merits further development as a clinical trial candidate for latent HIV-1 eradication.

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Published In

J Med Chem

DOI

EISSN

1520-4804

Publication Date

November 12, 2015

Volume

58

Issue

21

Start / End Page

8638 / 8646

Location

United States

Related Subject Headings

  • Virus Latency
  • Protein Kinase C beta
  • Medicinal & Biomolecular Chemistry
  • Leukocytes, Mononuclear
  • Humans
  • HIV-1
  • HIV Infections
  • Enzyme Activation
  • Diterpenes
  • CD4-Positive T-Lymphocytes
 

Citation

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Lai, W., Huang, L., Zhu, L., Ferrari, G., Chan, C., Li, W., … Chen, C.-H. (2015). Gnidimacrin, a Potent Anti-HIV Diterpene, Can Eliminate Latent HIV-1 Ex Vivo by Activation of Protein Kinase C β. J Med Chem, 58(21), 8638–8646. https://doi.org/10.1021/acs.jmedchem.5b01233
Lai, Weihong, Li Huang, Lei Zhu, Guido Ferrari, Cliburn Chan, Wei Li, Kuo-Hsiung Lee, and Chin-Ho Chen. “Gnidimacrin, a Potent Anti-HIV Diterpene, Can Eliminate Latent HIV-1 Ex Vivo by Activation of Protein Kinase C β.J Med Chem 58, no. 21 (November 12, 2015): 8638–46. https://doi.org/10.1021/acs.jmedchem.5b01233.
Lai W, Huang L, Zhu L, Ferrari G, Chan C, Li W, et al. Gnidimacrin, a Potent Anti-HIV Diterpene, Can Eliminate Latent HIV-1 Ex Vivo by Activation of Protein Kinase C β. J Med Chem. 2015 Nov 12;58(21):8638–46.
Lai, Weihong, et al. “Gnidimacrin, a Potent Anti-HIV Diterpene, Can Eliminate Latent HIV-1 Ex Vivo by Activation of Protein Kinase C β.J Med Chem, vol. 58, no. 21, Nov. 2015, pp. 8638–46. Pubmed, doi:10.1021/acs.jmedchem.5b01233.
Lai W, Huang L, Zhu L, Ferrari G, Chan C, Li W, Lee K-H, Chen C-H. Gnidimacrin, a Potent Anti-HIV Diterpene, Can Eliminate Latent HIV-1 Ex Vivo by Activation of Protein Kinase C β. J Med Chem. 2015 Nov 12;58(21):8638–8646.
Journal cover image

Published In

J Med Chem

DOI

EISSN

1520-4804

Publication Date

November 12, 2015

Volume

58

Issue

21

Start / End Page

8638 / 8646

Location

United States

Related Subject Headings

  • Virus Latency
  • Protein Kinase C beta
  • Medicinal & Biomolecular Chemistry
  • Leukocytes, Mononuclear
  • Humans
  • HIV-1
  • HIV Infections
  • Enzyme Activation
  • Diterpenes
  • CD4-Positive T-Lymphocytes