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Journal of Virology, May 2005, p. 6122-6133, Vol. 79, No. 10
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.10.6122-6133.2005

Discovery of Small-Molecule Human Immunodeficiency Virus Type 1 Entry Inhibitors That Target the gp120-Binding Domain of CD4

Quan-en Yang,¹ Andrew G. Stephen,² Joseph W. Adelsberger,³ Paula E. Roberts,¹ Weimin Zhu,¹ Michael J. Currens,⁴ Yaxiong Feng,⁵ Bruce J. Crise,⁶ Robert J. Gorelick,⁶ Alan R. Rein,⁵ Robert J. Fisher,² Robert H. Shoemaker,⁴ and Shizuko Sei^1*

Laboratory of Antiviral Drug Mechanisms,¹ Protein Chemistry Laboratory,² Clinical Services Program, SAIC-Frederick,³ Screening Technologies Branch,⁴ HIV Drug Resistance Program, NCI-Frederick,⁵ AIDS Vaccine Program, SAIC-Frederick, Frederick, Maryland⁶

Received 14 October 2004/ Accepted 3 January 2005

The interaction between human immunodeficiency virus type 1 (HIV-1) gp120 and the CD4 receptor is highly specific and involves relatively small contact surfaces on both proteins according to crystal structure analysis. This molecularly conserved interaction presents an excellent opportunity for antiviral targeting. Here we report a group of pentavalent antimony-containing small molecule compounds, NSC 13778 (molecular weight, 319) and its analogs, which exert a potent anti-HIV activity. These compounds block the entry of X4-, R5-, and X4/R5-tropic HIV-1 strains into CD4⁺ cells but show little or no activity in CD4-negative cells or against vesicular stomatitis virus-G pseudotyped virions. The compounds compete with gp120 for binding to CD4: either immobilized on a solid phase (soluble CD4) or on the T-cell surface (native CD4 receptor) as determined by a competitive gp120 capture enzyme-linked immunosorbent assay or flow cytometry. NSC 13778 binds to an N-terminal two-domain CD4 protein, D1/D2 CD4, immobilized on a surface plasmon resonance sensor chip, and dose dependently reduces the emission intensity of intrinsic tryptophan fluorescence of D1/D2 CD4, which contains two of the three tryptophan residues in the gp120-binding domain. Furthermore, T cells incubated with the compounds alone show decreased reactivity to anti-CD4 monoclonal antibodies known to recognize the gp120-binding site. In contrast to gp120-binders that inhibit gp120-CD4 interaction by binding to gp120, these compounds appear to disrupt gp120-CD4 contact by targeting the specific gp120-binding domain of CD4. NSC 13778 may represent a prototype of a new class of HIV-1 entry inhibitors that can break into the gp120-CD4 interface and mask the gp120-binding site on the CD4 molecules, effectively repelling incoming virions.

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* Corresponding author. Mailing address: Laboratory of Antiviral Drug Mechanisms, Screening Technologies Branch, Developmental Therapeutics Program, SAIC-Frederick, NCI-Frederick, Bldg. 439, P.O. Box B, Frederick, MD 21702. Phone: (301) 846-1780. Fax: (301) 846-6067. E-mail: sei{at}dtpax2.ncifcrf.gov.

Supplemental material for this article may be found at http://jvi.asm.org/.

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Journal of Virology, May 2005, p. 6122-6133, Vol. 79, No. 10
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.10.6122-6133.2005

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