The broad, long-term goal of the work described in this proposal is to develop general strategies for the production of therapeutic nucleic acid binding molecules. The proposed studies will utilize a series of new DNA-binding molecules that the PI has named """"""""serpentercalators"""""""" because of the snake-like form the longer ones assume when bound to nucleic acid duplexes. Serpentercalators have very high affinity for DNA, can block in vitro the activities of several key enzymes, and are synthesized using solid phase techniques. Thus, serpentercalators represent the best nucleic acid binding system currently available for carrying out combinatorial work. Two different combinatorial approaches will be investigated: 1) When coupled to an appropriate binding assay, so-called """"""""needle in the molecular haystack"""""""" experiments can be used to identify members of a library that have important biological activity.
Specific aims 1 -3 of the proposal exploit this aspect of combinatorial libraries to identify serpentercalators with high affinity and specificity for important nucleic acid sequences. Because of the serpentercalators' novel design, the vast majority of the proposed library members will possess the ability to bind nucleic acids with high affinity. Thus, the proposed """"""""molecular haystacks"""""""" of serpentercalators should be very fertile. 2) Another powerful attribute of combinatorial libraries is that they provide for the comprehensive identification of correlations between molecular properties and biological activity. In the proposed approach (specific aim 4), serpentercalator libraries will be fractionated by chromatography according to important molecular properties (e.g. hydrophobicity, charge etc.); then, the fractions will be screened for trends in cancer cell line cytotoxic activity. Using this approach, truly comprehensive molecular property-cytotoxicity relationships will be conclusively identified. The resulting relationships will serve as the basis for enriching subsequent libraries with improved properties, providing an iterative approach to optimized molecules. The bottom line is that the proposed comprehensive studies will provide tremendous insight into how amino acids can modulate sequence specificity in nucleic acid binding and to what extent gross molecular properties control cytotoxicity within a series of chemotherapeutic agents. In addition, a number of potentially very important anticancer and antiviral chemotherapeutic lead compounds will be produced and characterized.
| Lee, Jeeyeon; Guelev, Vladimir; Sorey, Steven et al. (2004) NMR structural analysis of a modular threading tetraintercalator bound to DNA. J Am Chem Soc 126:14036-42 |
| Guelev, Vladimir; Sorey, Steven; Hoffman, David W et al. (2002) Changing DNA grooves--a 1,4,5,8-naphthalene tetracarboxylic diimide bis-intercalator with the linker (beta-Ala)(3)-Lys in the minor groove. J Am Chem Soc 124:2864-5 |
| Guelev, V; Lee, J; Ward, J et al. (2001) Peptide bis-intercalator binds DNA via threading mode with sequence specific contacts in the major groove. Chem Biol 8:415-25 |
| Murr, M M; Harting, M T; Guelev, V et al. (2001) An octakis-intercalating molecule. Bioorg Med Chem 9:1141-8 |
| Guelev, V M; Harting, M T; Lokey, R S et al. (2000) Altered sequence specificity identified from a library of DNA-binding small molecules. Chem Biol 7:8-Jan |
