Retro peptide-hybrids as selective inhibitors of the Dengue virus NS2B-NS3 protease

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• 作者：Christoph Nitsche^a ; Mira A.M. Behnam^b ; Christian Steuer^a ; Christian D. Klein^a ; ^{c.klein@uni-heidelberg.de}
• 关键词：Hybrid retro peptides ; Dengue virus ; West Nile virus ; Thrombin ; NS2B-NS3 protease
• 刊名：Antiviral Research
• 出版年：2012
• 期刊代码：7_01663542
• 类别：imm
• 出版时间：April, 2012
• 卷：94
• 期：1
• 页码：72-79
• 文件大小：391 K

摘要

New chemotherapeutics against Dengue virus and related flaviviruses are of growing interest in antiviral drug discovery. The viral serine protease NS2B-NS3 is a promising target for the development of such agents. Drug-like inhibitors of this protease with high affinity to the target are not available at the moment. The present work describes the discovery of new retro di- and tripeptide hybrids that do not necessarily require an electrophilic 鈥渨arhead鈥?to achieve affinities in the low micromolar range. The most active sequence in this series is the tripeptide R-Arg-Lys-Nle-NH₂. By variation of the N-terminal groups (R) it could be shown that the previously described arylcyanoacrylamide moiety is a preferable group in this position. Retro tripeptide hybrids were found to be more active and more selective than retro dipeptide hybrids. A significant selectivity towards the Dengue virus protease could be shown in a counterscreen with thrombin and the West Nile virus protease. Alternative sequences to R-Arg-Lys-Nle-NH₂ did not have higher affinities towards the Dengue virus protease, similar to retro-inverse sequences with d-lysine and d-arginine residues. The results of a competition assay with the known inhibitor aprotinin indicate that the N-terminal arylcyanoacrylamide residue of this compound class binds near the catalytic center of the enzyme.