Sulfated polymannuroguluronate inhibits Tat-induced SLK cell adhesion via a novel binding site, a KKR spatial triad.

Abstract

AIM:

Sulfated polymannuroguluronate (SPMG), a candidate anti-AIDS drug, inhibited HIV replication and interfered with HIV entry into host T lymphocytes. SPMG has high binding affinity for the transactivating factor of the HIV-1 virus (Tat) via its basic domain. However, deletion or substitution of the basic domain affected, but did not completely eliminated Tat-SPMG interactions. Here, we sought to identify other SPMG binding sites in addition to the basic domain.

METHODS:

The potential SPMG binding sites were determined using molecular simulation and a surface plasmon resonance (SPR) based competitive inhibition assay. The effect of SPMG on Tat induced adhesion was evaluated using a cell adhesion assay.

RESULTS:

The KKR domain, a novel high-affinity heparin binding site, was identified, which consisted of a triad of Lys12, Lys41, and Arg78. The KKR domain, spatially enclosed SPMG binding site on Tat, functions as another binding domain for SPMG. Further functional evaluation demonstrated that SPMG inhibits Tat-mediated SLK cell adhesion by directly binding to the KKR region.

CONCLUSION:

The KKR domain is a novel high-affinity binding domain for SPMG. Our findings provide important new insights into the molecular mechanisms of SPMG and a potential therapeutic intervention for Tat-induced cell adhesion.

• Authors: Yan-lin Wu, Jing Ai, Jing-ming Zhao, Bing Xiong, Xiao-jie Xin, Mei-yu Geng, Xian-liang Xin, Han-dong Jiang
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 32 Issue 5 Pg. 647-54 (May 2011) ISSN: 1745-7254 [Electronic] United States
• PMID: 21499289 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-HIV Agents
• Polysaccharides
• sulfated polymannuroguluronate
• tat Gene Products, Human Immunodeficiency Virus
• Heparin

Topics

• Anti-HIV Agents (pharmacology)
• Binding Sites
• Cell Adhesion (drug effects)
• Cell Line, Tumor
• Heparin (metabolism)
• Humans
• Polysaccharides (pharmacology)
• Sarcoma, Kaposi (metabolism, pathology)
• Surface Plasmon Resonance
• tat Gene Products, Human Immunodeficiency Virus (metabolism)