Elucidation of structural and physico-chemical factors resulting in nucleic acid recognition
Design and synthesis of quinoxaline antibiotics for extended sequence recognition.
Design and assessment of oligonucleotide and peptide nucleic acids for therapeutics and relevant cell delivery systems
By developing a concerted approach to molecular recognition of DNA/RNA, gene targeting and allied phenomena the partners intend to provide new insights and therapeutics for treatment of genetically-based disease, particularly cancer. The program is conceived over a broad front, but always with the unifying principle of specificity at the DNA level as its common theme. Computer modelling and drug design guided by the latest understanding of principles of molecular recognition will be complemented by a rigorous programme of experimental investigations aimed at elucidating and refining our knowledge of the fundamental rules which govern ligand binding to specific nucleotide sequences/genetic elements. The roles of digital (sequence) and analogue (conformation) readout of DNA will be dissected through studies of known DNA ligands interacting with various sequences. The early stages will be focused on developments related to existing DNA ligands, e.g., minor groovebinders, polyfunctional intercalators, composite/hybrid molecules, and peptide nucleic acids (PNA). Subsequently, new types of ligands, new nucleobases for incorporation into PNA and so on will be actively sought to expand the repertoire of exploitable avenues for sequence-specific recognition. At the next level of complexity the kinetics, thermodynamics and structural consequences of specific interactions with DNA as they relate to gene targeting will be investigated and a variety of in vitro systems carefully chosen to yield results of practical value will be employed. Gene constructs of special relevance to cancer, HIV, and other disorders having a genetic basis will be used as substrates to investigate such questions as the accuracy of discrimination, the means to recognise tracts of nucleotides other than polypurine runs, and how recA-assisted sequence recognition may be turned to advantage. At all levels the possible contribution of small molecules as adjuncts to enhance specificity, efficacy and stability will be examined to assess their role in securing the right pharmacological profile. This work will lead on to biological studies involving cell-free preparations, cell uptake measurements, animal experiments and preparation for clinical trials. Systems based on the Ha-ras oncogene and its various mutations. the pml/RARa fusion protein, and the bc12 gene which are characteristically associated with important human cancers will provide excellent substrates for biological testing directly relevant to vitally important problems in therapeutic medicine and diagnosis.
Funding SchemeCSC - Cost-sharing contracts
2200 Kobenhavn N
106 91 Arr Stockholm
CB2 1TT Cambridge