Educational Background:

PhD, University of Cambridge, 1965 MSc, Victoria University of Wellington, 1960

Awards:

• New Zealand Institute of Chemistry Prize • National Institutes of Health Career Development Award • Co-chairman, Life Sciences Task Group; Space Science Board, National Academy of Sciences: "Space Science in the Twenty-first Century: Imperatives for the Decades 1995 to 2015" • International Society for the Study of the Origin of Life (Councillor)

Research Description:

We have made a new amide-linked oligonucleotide analog which retains the furanose rings of natural nucleic acids but which uses three atoms to span the distance between sugar rings instead of the four found in naturally-occurring RNA and DNA. Two dimers, UNHU and ANHA, containing the novel amide linkage have been synthesized, and the latter has been shown to bind to poly(U). We now plan to study solid-support synthesis of specific sequences, binding specificity, template reactions, and diagnostic and therapeutic applications of these analogs.

Discoveries made during the last fifteen years have revolutionized our understanding of the diverse roles that RNA plays in biological systems. However, methodologies for the chemical synthesis of oligoribonucleotides on solid phase supports have not kept pace with advances in DNA synthesis. We have developed a new type of 2'-hydroxyl protecting group for the automated machine synthesis of RNA oligomers: a 2-hydroxyisophthalate formaldehyde acetal (HIFA). The unique feature of this protecting group is that as the bis ester it is relatively stable to the acidic conditions that are used for repeated removal of dimethoxytrityl groups during chain elongation. However, the final deprotection step in alkali, which cleaves the chain from the support and removes the base and phosphate protecting groups, converts it to the bis carboxylate, and this can be removed relatively rapidly by treatment with mild acid. We are now modifying the isophthalate ring to increase the rate of acid-catalyzed deprotection. Other research interests are site-specific reactions of nucleic acids, mechanisms of phosphate ester hydrolysis, reactions on oligonucleotide templates, and the de novo synthesis of RNA under simulated prebiotic conditions.Naturally-occurring RNAAmide-linked analog

Selected Publications:

McHale, A. H.; Usher, D. A. Hydrolytic stability of helical RNA: A selective advantage for the natural 3',5' bond. Proc. Natl. Acad. Sci. U.S.A. 1976, 73, 1149.

Ferris, J. P.; Usher D. A. Origin of life, in Biochemistry, 2nd ed. Zubay, G., ed., Macmillan: New York, 1988.

Rastogi, H.; Usher, D. A. A new 2'-hydroxyl protecting group for the automated synthesis of oligoribonucleotides. Nucleic Acids Res. 1995, 23, 4872.

Harris, M.; Usher, D. A. A new amide-linked polynucleotide analog. Origins Life Evol. Biosphere 1996, 26, 398.

Before Antisense. Antisense and Nucleic Acid Drug Development 1997, 7, 445.