题 目：New strategies and new targets to combat drug resistance in HIV Chemotherapy: Chemistry meets Virology

报告人：Prof. Dr. Chris Meier ，Organic Chemistry, Department of Chemistry, Faculty of Science, University of Hamburg

时 间：2014年6月19日，下午3：40-5：10

地 点：化学馆241

Prof. Dr. Chris Meier

Organic Chemistry, Department of Chemistry, Faculty of Science, University of Hamburg, Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany; e-mail: chris.meier@chemie.uni-hamburg.de

Since the first diagnosis of AIDS in 1981 great efforts were made to treat HIV infections. Among the strategies, the introduction of HAART in the mid ‘90s was an important improvement in combating HIV. HAART drugs primarily target the viral enzymes. However, the occurrence of drug resistance and potential side-effects in long-term HAART require the search for new targets and subsequent development of novel drugs.

One still up-to-date option is the use of nucleoside analogues as potent RNA/DNA-polymerases. Several examples are known and are used very successfully in the clinic, e.g. d4T. In addition to nucleoside analogues bearing a glycon-moiety, carbocyclic nucleosides showed also interesting antiviral properties. We reported on the carbocyclic 2´-deoxy­thymidine (carba-dT 1), which proved highly active against several viruses, e.g. HIV-1. Primer extension assays using RNA-templates and reverse transcriptase revealed a new mechanism of the inhibition in which DNA synthesis was blocked by a so-called delayed chain termination. This makes D-carba-dT a very promising lead for the development of an antiviral that will be effective against nucleoside-reverse transcriptase-inhibitor (NRTI)-resistant viruses.

Secondly, cellular cofactors as the eukaryotic initiation factor 5A (eIF‑5A) play an important role in the HIV replication cycle. eIF‑5A is involved in the transport of the unspliced spliced viral mRNAs from the nucleus to the cytoplasm. A unique post-translational modification of a specific lysine residue to the unusual amino acid hypusine by two human enzymes (deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH)) is mandatory for activation of eIF-5A (see Scheme). CNI-1493 efficiently inhibits DHS and thereby suppressing HIV replication. The synthesis, the evaluation of DHS inhibition and the in vitro-inhibitory potency on HIV-1 replication of several CNI-1493 derivatives will be discussed. Finally, structure-based drug design approaches were applied for the development of novel, active-site DHS inhibitors showing marked inhibitory activity against DHS.