Retro peptide-hybrids as selective inhibitors of the Dengue virus NS2B-NS3 protease
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 availab...
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| Main Authors: | , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
26 February 2012
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| In: |
Antiviral research
Year: 2012, Volume: 94, Issue: 1, Pages: 72-79 |
| ISSN: | 1872-9096 |
| DOI: | 10.1016/j.antiviral.2012.02.008 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1016/j.antiviral.2012.02.008 Verlag, Volltext: http://www.sciencedirect.com/science/article/pii/S0166354212000411 
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| Author Notes: | Christoph Nitsche, Mira A.M. Behnam, Christian Steuer, Christian D. Klein |
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| 520 | |a 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. | ||
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