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L.M. Viranga Tillekeratne |
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Institutions/Degrees
| B.S., 1969 | University of Colombo, Sri Lanka |
| D.Phil., 1975 | Oxford University |
| Postdoctoral Research Associate, 1982 | University of Oklahoma |
Research Interests
We are interested in the study of molecular probes, of both synthetic and natural origin, to study protein function as a basis for drug design.
We are currently investigating a new class of inhibitors of the human immunodeficiency virus-1 reverse transcriptase. These synthetic analogues, obtained by systematic and structure-activity based rational optimization of a natural product, inhibit the wild type as well as a double mutant form of HIV-1 reverse transcriptase, insensitive to other noncompetitive inhibitors. Of special interest is a sub-class of these agents that inhibits the strand transfer process during reverse transcription. Such inhibitors have potential as therapeutic agents expected to reduce the rate of recombination-associated mutations, a major cause of induced drug resistance in HIV-1. Another class of compounds we are currently investigating is affinity-directed redox-active agents. These compounds possessing the choline sub-unit interact with choline- or acetylcholine-binding macromolecules and are useful in studying the underlying processes of acetylcholine-mediated neurotransmission.
We have also been studying the mechanism of catalytic action of pyrroloquinoline quinone (PQQ) aza-analogues. PQQ, which is a redox-reactive cofactor for a variety of enzymes that catalyze oxidation-reduction reactions in prokaryotes, appears to be an important cofactor in eukaryotes as well. It seems to be a micro-nutrient in vertebrates, equivalent in importance to biotin and vitamin K. We have synthesized and studied the three isomeric, isosteric aza-analogues of PQQ, which are useful mechanistic probes for studying the underlying mechanisms of enzymatic reactions catalyzed by PQQ. We are currently focusing our attention on studies with the enzyme flavin reductase, which utilizes PQQ in preference to riboflavin. As such enzymes mediate the continuous reduction of oxidized hemoglobin in erythrocytes and further protect against reoxygenation injury in both the heart and brain, structural analogues of PQQ may possess the potential for use as therapeutic agents in heart attack and stroke.
Representative Publications
