C-Terminal residue optimization and fragment merging: discovery of a potent peptide-hybrid inhibitor of Dengue protease
Dengue virus protease is a promising target for the development of antiviral drugs. We describe here a two-step rational optimization that led to the discovery of the potent inhibitor 35 with nanomolar binding affinity at dengue protease serotype 2 (IC50 = 0.6 μM, Ki = 0.4 μM). First, a large number...
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| Main Authors: | , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
July 18, 2014
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| In: |
ACS medicinal chemistry letters
Year: 2014, Volume: 5, Issue: 9, Pages: 1037-1042 |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/ml500245v |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1021/ml500245v
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| Author Notes: | Mira A. M. Behnam, Christoph Nitsche, Sérgio M. Vechi, Christian D. Klein |
| Summary: | Dengue virus protease is a promising target for the development of antiviral drugs. We describe here a two-step rational optimization that led to the discovery of the potent inhibitor 35 with nanomolar binding affinity at dengue protease serotype 2 (IC50 = 0.6 μM, Ki = 0.4 μM). First, a large number of natural and non-natural amino acids were screened at the C-terminal position of the previously reported, canonical peptide sequence (Cap-Arg-Lys-Nle-NH2). Compared to the reference compound 1 (Bz-Arg-Lys-Nle-NH2, IC50 = 13.3 μM), a 4-fold higher inhibitory potential was observed with the incorporation of a C-terminal phenylglycine (compound 9, IC50 = 3.3 μM). Second, we applied fragment merging of 9 with the previously reported thiazolidinedione peptide hybrid 33 (IC50 = 2.5 μM). This approach led to the fusion of two inhibitor-fragments with micromolar affinity into a 20-fold more potent, competitive inhibitor of dengue protease. |
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| Item Description: | Gesehen am 04.09.2020 |
| Physical Description: | Online Resource |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/ml500245v |