Prof. Dr. Chris Meier

Hamburg University, Germany

报告时间：6月13日 15:00-16:30

报告地点：6号楼 宣讲厅

邀请人：商明 副教授

报告人简介

Chris Meier was trained in Chemistry at the University of Marburg, Germany, finishing his Ph.D. in 1989. He moved to the Pasteur Institute for a PostDoc stay and joined Frankfurt University in 1991 as an Assistant Professor until 1996. He was appointed as Associate Professor at Würzburg University in 1997. In 1999, he received a full professorship offer from Hamburg University, where he has worked ever since. His research focuses on nucleoside/nucleotide and pronucleotide chemistry and small molecule inhibitors in antiviral drug discovery (Medicinal Chemistry also using Structure Biology methods). Moreover, he is working on membrane permeable derivatives of second messenger adenine nucleotides (Chemical Biology).

报告摘要

Over the last decades a number of nucleoside analogues were clinically used in antiviral chemotherapy. However, often the antiviral potency of the nucleoside analogues is limited due to the lack of intracellular phosphorylation into the triphosphorylated forms by cellular kinases. In our work, d4TTP prodrugs with different aliphatic masking units have been synthesized via two different routes based on phosphoramidite or H-phosphonate chemistry. Our triphosphate delivery system is comprised of enzymatically cleavable masking groups (acyloxybenzyl-moieties) which are attached to the g-phosphate group. Chemical hydrolysis and esterase studies, enzymatic cleavage in CEM/0 cell extract, primer extension assays, PCR assays, whole-cell incubations and antiviral HIV tests will be discussed which proved the successful delivery of NTPs. This TriPPPro-concept opens up unknown possibilities not only in Medicinal Chemistry but also in Chemical Biology. Next, a prodrug approach in which the g-phosphate of NTPs is modified by two different groups was developed. In antiviral assays, these compounds were highly potent against HIV-1 and HIV-2 in thymidine kinase-deficient CD4+ T-cells (CEM/TK–). Primer extension assays using HIV’s reverse transcriptase and different cellular human DNA-polymerases showed that the new compounds act as a substrate for RT but were found to be non-substrates for cellular DNA-polymerases b and g . Finally, also prodrugs bearing two alkyl groups in the terminal phosphate group will be presented and compared to the former two concepts.