Our long range goal is the design and synthesis of organic molecules which bind to specific DNA sequences. Our first immediate subgoal is to characterize the solution structure of a new DNA conformation we have discovered, a dinucleotide repeat structure which is induced by binding certain steroid diamines (which we have synthesized) to poly(dA-dT). Using NMR and CD to probe DNA conformation we will synthesize new ligands to see what structural features of the steroid diamine promote conformational change in poly (dA-dT). We will chemically synthesize small DNA oligomers to discover what sequences can exist in this new conformation, using NMR to obtain details of the drug-DNA solution structure. We will enzymatically make DNA with alternating phosphate and phosphothioate diester backbones (eq. ApTp(s)...) to see which phosphorous, the d(ApT) or the (TpA) goes over to a new conformation in poly (dA-dT). We will also compare the reactivity with alkylating agents of B-form poly (dA-dT) and our alternating form. We also propose to synthesize new linked drugs containing netropsin and anthramycin fragments. These linked groove binders should exhibit unprecedented sequence selectivity by a synthetic molecule. We will assay selectivity by the drug's differential inhibition of site selectivity of particular restriction enzymes.
| Suggs, J W; Wagner, R W (1986) Nuclease recognition of an alternating structure in a d(AT)14 plasmid insert. Nucleic Acids Res 14:3703-16 |
| Suggs, J W; Taylor, D A (1985) Use of phosphorothioate analogs of poly(dA-dT).poly(dAdT) to study steroidal-diamine induced conformational change in poly(dA-dT).poly(dA-dT). FEBS Lett 189:77-80 |
| Suggs, J W; Taylor, D A (1985) Evidence for sequence-specific conformational changes in DNA from the melting temperatures of DNA phosphorothioate derivatives. Nucleic Acids Res 13:5707-16 |
