Novel HIV Tat antagonists

Abstract

HIV-1 Tat protein plays one of the central roles in AIDS pathogenesis due to its principle function in HIV-1 transcription and multiple involvement in HIV progression. For example, Tat acts as immunosuppressor, activator of quiescent T cells for productive HIV-1 infection and it is a chemokine analog. Tat upregulates the expression of chemokine receptors (CXCR4 and CCR5) which serve as coreceptors of HIV-1 entry to cells. Tat mediates some AIDS-associated pathological processes, e.g., Kaposi's sarcoma, main neoplastic manifestation of AIDS. The discovery of novel HIV Tat antagonists is not just one more strategy in the anti-HIV pharmacological intervention, but is most important in view of the inability of the existing therapies to eradicate HIV infection. The main efforts in this field are aimed at the disruption of Tat-TAR interaction and HIV transactivation inhibition. A set of compounds of various chemical natures were recently discovered in this field. Mimicking the Tat basic peptide comprises one of the modern approaches for the design of Tat antagonists. Several Tat basic peptide mimetic compounds possess significant antiviral activity. A novel class of Tat antagonists are aminoglycoside-arginine conjugates, that not only inhibit HIV replication but efficiently compete with several Tat functions, which are of primary importance in HIV/AIDS pathogenesis. Drug Dev. Res. 50:502–515, 2000. © 2000 Wiley-Liss, Inc.