DESIGN AND ANALYSIS OF MOLECULAR MOTIFS FOR SPECIFIC RECOGNITION OF RNA

Selective targeting of RNA has become a recent priority in, drug desig n strategies due to the emergence of retroviruses, the need for new an tibiotics to counter drug resistance, and our increased awareness of t he essential role RNA and RNA structures play in the progression of di sease. Most organic compounds known to specifically target RNA are com plex, naturally occurring antibiotics that are difficult to synthesize or derivatize and modification of these compounds to optimize interac tions with structurally unique RNAs is difficult. The de novo design o f synthetically accessible analogues is one possible alternative; howe ver, little is known about the RNA recognition principles on which to design new compounds and limited information on RNA structure in gener al is available. To contribute to the growing body of knowledge on RNA recognition principles, we have prepared two series of polycationic R NA-binding agents, one with a linear scaffold, the other with a macroc yclic scaffold. We evaluated these compounds for their ability to bind to DNA and RNA, as well as to a specific RNA, the regulatory sequence , RRE, derived from HIV-1, by using thermal melting, circular dichrois m, and electrophoresis gel shift methods. Our results suggest that cat ionic charge centers of high pK(a) that are displayed along a scaffold of limited flexibility bind preferentially to RNA, most likely within the major groove. Related derivatives that bind more strongly to DNA more closely mimic classical DNA minor-groove binding agents. Several of the macrocyclic polycations expand on a new binding motif where pur ine bases in duplex RNA are complexed within the macrocyclic cavity, e nhancing base-pair opening processes and ultimately destabilizing the RNA duplex. The results in this report should prove a helpful addition to the growing information on molecular moths that specifically bind to RNA. (C) 1997 Elsevier Science Ltd.