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Currently, research in our group focuses on drug design and synthesis. Our synthesis work centers on development of molecules that selectively interact with nucleic acids, which is hypothesized to lead to the observed biological activity. Synthetic work underway is directed toward discovery of new therapeutic agents for treatment of a variety of infectious diseases. These projects involve important collaborations with other scientists at Georgia State University, at other universities and institutes, and in industry.
Our approach to development of new antimicrobial agents is based upon the ability of certain diaryldiamidines (dications) to bind selectively to the minor groove of AT regions of DNA and thereby inhibit one or more DNA dependant enzymes such as the topoisomerases. Molecules selected for synthesis include the following features: (a) dicationic; (b) a shape that complements the minor groove of B-DNA; (c) recognition units (H-bond donors and acceptors) on the edge of the molecule facing the floor of the groove; and (d) variable bulk on the outer edge of the molecule. Recently, we have shown that certain linear diamidines also can bind in the minor groove with high affinity thus broadening the conventional design strategy. Since these dicationic molecules do not have good oral bioavailability an important part of our research program is directed toward developing orally effective prodrugs for the diamidines. Our current emphasis is on protozoan diseases and AIDS related opportunistic diseases. One of our prodrugs was in two Phase III clinical trials; one for human African trypanosomiasis and the other for Pneumocystis carinii pneumonia, however it has recently been withdrawn due to toxicity.
Our approach to development of new antimicrobial agents is based upon the ability of certain diaryldiamidines (dications) to bind selectively to the minor groove of AT regions of DNA and thereby inhibit one or more DNA dependant enzymes such as the topoisomerases. Molecules selected for synthesis include the following features: (a) dicationic; (b) a shape that complements the minor groove of B-DNA; (c) recognition units (H-bond donors and acceptors) on the edge of the molecule facing the floor of the groove; and (d) variable bulk on the outer edge of the molecule. Recently, we have shown that certain linear diamidines also can bind in the minor groove with high affinity thus broadening the conventional design strategy. Since these dicationic molecules do not have good oral bioavailability an important part of our research program is directed toward developing orally effective prodrugs for the diamidines. Our current emphasis is on protozoan diseases and AIDS related opportunistic diseases. One of our prodrugs was in two Phase III clinical trials; one for human African trypanosomiasis and the other for Pneumocystis carinii pneumonia, however it has recently been withdrawn due to toxicity.
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HemaSphereno. 5 (2024)
Pathogens (Basel, Switzerland)no. 5 (2023): 701-701
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European journal of medicinal chemistry (2023): 115287-115287
ACS bio & med chem Auno. 4 (2023): 335-348
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Jana R. Jenquin, Alana P. O’Brien,Kiril Poukalov, Yidan Lu, Jesus A. Frias,Hannah K. Shorrock,Jared I. Richardson, Hormoz Mazdiyasni,Hongfen Yang,Robert W. Huigens,David Boykin,Laura P.W. Ranum,
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