title: Retro peptide-hybrids as selective inhibitors of the Dengue virus NS2B-NS3 protease.
abstract: 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 "warhead" to achieve affinities in the low micromolar range. The most active sequence in this series is the tripeptide R-Arg-Lys-Nle-NH(2). 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-NH(2) 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.
authors.affiliation: Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Nitsche
authors.forename: Mira A M
authors.initials: MA
authors.lastname: Behnam
authors.forename: Christian
authors.initials: C
authors.lastname: Steuer
authors.forename: Christian D
authors.initials: CD
authors.lastname: Klein
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D003715:Dengue / Q000188:drug therapy / Q000821:virology*; D003716:Dengue Virus / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D010455:Peptides / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D010455:Peptides; D012697:Serine Endopeptidases; D015842:Serine Proteinase Inhibitors; C504449:NS3 protease, dengue virus; D000085242:Viral Proteases