RNA TARGETING

       RNA Targets in HIV, Infectious Disease, and Cytokines RNA structure has become the focus for developing therapeutic strategies to regulate the expression of many disease-associated genes because any given RNA structure is unique to the gene from which it is expressed. However, the concept that RNA-directed compounds can confer a therapeutic impact is not new. For decades, antibiotics, like erythromycin, have been characterized to be bactericidal based on their capacity to bind to unique ribosomal RNA sequences in the bacterial 23S ribosome subunit. The B component of streptogramins inhibits peptide elongation in vivo during the early rounds of protein synthesis in a manner similar to that of the smaller microlides, including erythromycin. Ribotargets (Cambridge, UK) is a company that seeks to inhibit the essential TAT-Tar interaction to prevent HIV infection and AIDS.

     In this case, the TAT transactivating protein binds to the TAR stemloop at the viral LTR to promote viral growth. Blocking this interaction with selected compounds will interfere with the viral life cycle and be of therapeutic benefit. Scriptgen Inc. has a drug-discovery program directed to a single RNA target, the replication origin of hepatitis C virus. Message Pharmaceuticals (Malvern, PA), is the only company interested in diseaseassociated RNA targets of endogenously expressed genes . A major project in their program is to modulate cytokine expression as a therapeutic strategy for arthritis and cancer. Tumor necrosis factor (TNF) and interleukin-1 (IL-1) gene expression is up-regulated in the joints aof arthritis patients. Low molecular weight RNA-binding compounds can be screened for their capacity to inhibit binding of the AUF-1 to the AU-rich sequences in the 3'UTR of these cytokine mRNAs.

    Another class of drugs (CSAIDS) were previously shown to interfere with a kinase that phosphorylates the 3'UTR AUF-1, which controls cytokine mRNA stability in response to cellular signaling.