Design and synthesis of RNA-specific groove-binding cations: implications for antiviral drug design.
As as initial step in the design of structure-specific RNA-interactive molecules as potential antiviral agents, we have focused on the synthesis of molecules that exhibit strong and preferential binding to duplex RNA. A series of polycationic ligands have been synthesized, and the degree of preferential binding to RNA has initially been determined by thermal denaturation (delta Tm) with both RNA [poly(A).poly(U)] and DNA [poly(dA).poly(dT)] polymers at a variety of pH values. Seven compounds from the series exhibit a substantial degree of RNA-selective binding. The relatively high delta Tm values obtained suggest a specific mode of interaction between these ligands and the RNA helix. By contrast, the much lower delta Tm values with poly(dA).poly(dT) DNA reflect a more nonspecific interaction mode. A viscometric titration study with poly(A).poly(U) confirms that they do not bind by intercalation. The results, combined with the known structure and electronegative potential of duplex RNA, suggest that these molecules bind in the major groove via specific electrostatic and/or hydrogen-bonded interactions.
McConnaughie
A W
AW
Department of Chemistry, Georgia State University, Atlanta 30303.
Spychala
J
J
Zhao
M
M
Boykin
D
D
Wilson
W D
WD
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D002412:Cations; D004247:DNA / Q000378:metabolism; D015195:Drug Design; D004563:Electrochemistry; D006358:Hot Temperature; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D011061:Poly A / Q000378:metabolism; D011071:Poly T / Q000378:metabolism; D011067:Poly dA-dT / Q000378:metabolism; D011489:Protein Denaturation; D012313:RNA / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D002412:Cations; D011061:Poly A; D011071:Poly T; D011067:Poly dA-dT; C008950:poly A-T; D012313:RNA; D004247:DNA