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

• Verfasst von: Nitsche, Christoph [VerfasserIn]
• Verfasst von: Behnam, Mira A. M. [VerfasserIn]
• Verfasst von: Steuer, Christian [VerfasserIn]
• Verfasst von: Klein, Christian D. [VerfasserIn]
• Titel: Retro peptide-hybrids as selective inhibitors of the Dengue virus NS2B-NS3 protease
• Verf.angabe: Christoph Nitsche, Mira A.M. Behnam, Christian Steuer, Christian D. Klein
• E-Jahr: 2012
• Jahr: 26 February 2012
• Umfang: 8 S.
• Fussnoten: Gesehen am 11.06.2018
• Titel Quelle: Enthalten in: Antiviral research
• Ort Quelle: Amsterdam [u.a.] : Elsevier Science, 1981
• Jahr Quelle: 2012
• Band/Heft Quelle: 94(2012), 1, Seite 72-79
• ISSN Quelle: 1872-9096
• DOI: doi:10.1016/j.antiviral.2012.02.008
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Dengue virus
• Sach-SW: Hybrid retro peptides
• Sach-SW: NS2B-NS3 protease
• Sach-SW: Thrombin
• Sach-SW: West Nile virus
• K10plus-PPN: 1576212165

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-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.