Klimkait T, Lazdins J, Zeller M, Hamy F; International Conference on AIDS.

Int Conf AIDS. 2000 Jul 9-14; 13: abstract no. WeOrA537.

T. Klimkait, University of Basel, Institute for med. Microbiologie, Petersplatz 10, 4003 Basel, Switzerland, Tel.: +41 61 267 3264, Fax: +41 61 267 3298, E-mail: thomas.klimkait@unibas.ch

Background: Rapid development of viral drug resistance poses a serious limitation to the management of HIV disease and to pharmaceutical drug programs. In turn, this obstacle forms a basis for new efforts utilizing alternative viral targets. By aiming at the Tat-driven process of HIV gene regulation we searched for novel inhibitory concepts. We discovered a new class of compounds for this RNA-binding protein, and also an unexpected inhibitor target. Results: In sharp contrast to previous "Tat-antagonists" (e.g. Ro53335) we have identified a "true Tat inhibitor", which has no affinity for nucleic acids but potently inhibits classical Tat/TAR complexation and subsequent transactivation. This feature may contribute to its very favorable toxicity profile. In vitro data on this stilbene derivative CGA137053 demonstrate strict target selectivity and potent antiviral activity in primary human lymphocytes or macrophages, and show that it inhibits HIV-1, HIV-2 and SIV. Structure and molecular modeling/dynamics suggest that CGA137053 binds directly to Tat protein. As new and exciting second property the compound also antagonizes a TAR-independent activity of free Tat protein. Our experiments demonstrate that the rapidly induced CXCR4-mRNA expression by recombinant Tat protein (Huang et al. JVi.72,8952) can be fully suppressed by our inhibitor candidate. Conclusions: We have identified a potent, double-hitting, and chemically feasible Tat antagonist which possesses high target specificity and low cytotoxicity. It is not restricted to the Tat/TAR axis of HIV inhibition and is highly active on HIV-infected, primary human cells. As >90% of peripheral leukocytes are in a non-activated (CXCR4-negative) state, a block of CXCR4 surface expression may be of particular interest to control rapid viral replication to high titers in this body compartment. Based on these properties, we have hope that this novel HIV-inhibitory concept will have bearing for a next generation inhibitor.

Publication Types:

• Meeting Abstracts

Keywords:

• AIDS Vaccines
• Acquired Immunodeficiency Syndrome
• Antiviral Agents
• Gene Products, tat
• Genes, tat
• HIV Infections
• HIV Seropositivity
• HIV-1
• HIV-2
• Humans
• In Vitro
• Lymphocytes
• Macrophages
• Receptors, CXCR4
• Trans-Activation (Genetics)
• genetics

Other ID:

• GWAIDS0002614

UI: 102240108

From Meeting Abstracts