AEGiS-15IAC: A new class of small-molecule HIV entry inhibitors that target the gp120-binding domain of CD4.

15th International AIDS Conference

Bangkok, Thailand - July 11-16, 2004

A new class of small-molecule HIV entry inhibitors that target the gp120-binding domain of CD4.

Int Conf AIDS 2004 Jul 11-16; 15:(abstract no. WeOrA1308)

Sei S, Yang Q, Roberts P, Zhu W, Stephen A, Adelsberger J, Currents M, Feng Y, Fisher R, Rein A, Shoemaker R
Laboratory of Antiviral Drug Mechanisms, SAIC/NCI-Frederick, Frederick, MD 21702, United States

BACKGROUND: The interaction between HIV gp120 and the CD4 receptor is highly specific and involves considerably small contact surface areas. This step has been targeted by various CD4-mimicking proteins, antibodies and gp120-binders, although their in vivo efficacy has yet to be shown.

METHODS: Through antiviral characterization of lead compounds selected from various retroviral molecular target screenings of the NCI chemical library, we identified a group of antimony-containing small-molecule compounds that exerted a potent anti-HIV activity by blocking viral entry. We further sought to determine the target molecule, focusing on viral envelope-receptor interaction.

RESULTS: The compound, NSC 13778 (M. W. 319), and several analogs inhibited HIV infection in CEM-SS cells with EC50 of 0.63 ± 0.06 ~ 8.75 ± 1.25 muM (mean ± SD) and CC50 >400 muM. Their significant anti-HIV activity was similarly demonstrated in MAGI cells. However, the activity was sub stantially reduced if compound addition was delayed for more than 2 hours. The compounds also blocked the fusion of viral receptor-expressing MAGI cells and viral envelope-expressing HL2/3 cells. Using a competitive capture ELISA method, we found that NSC 13778 analogs significantly decreased the amount of gp120 bound to solid phase sCD4, but not that of sCD4 bound to solid phase gp120, indicating the compounds most likely competed with gp120 for CD4-binding. FACS analysis also showed that the binding of rgp120 on the CEM-SS cell surface was substantially abrogated in the presence of NSC 13778 analogs. Moreover, CEM-SS cells incubated with the compounds alone had decreased reactivity to anti-CD4 mAbs known to recognize gp120-binding site.

CONCLUSIONS: In contrast to the majority of previously developed viral entry inhibitors, NSC 13778 analogs appear to inhibit HIV infection by targeting the gp120-binding domain of host CD4 molecules. Further efforts are warranted to explore potential therapeut ic applications. (Supported in part by NCI Contract No. NO1-CO-12400)

Keywords: AEGIS, HIV Envelope Protein gp120, Antigens, CD4, Acquired Immunodeficiency Syndrome, HIV Infections, HIV Seropositivity, Antiviral Agents, immunology, pharmacokinetics, metabolism

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