Dual inhibitors of the dengue and West Nile virus NS2B-NS3 proteases: Synthesis, biological evaluation and docking studies of novel peptide-hybrids

Allan Bastos Lima; Mira A M Behnam; Yasmin El Sherif; Christoph Nitsche; Sergio M Vechi; Christian D Klein

doi:10.1016/j.bmc.2015.07.012

Dual inhibitors of the dengue and West Nile virus NS2B-NS3 proteases: Synthesis, biological evaluation and docking studies of novel peptide-hybrids

Bioorg Med Chem. 2015 Sep 1;23(17):5748-55. doi: 10.1016/j.bmc.2015.07.012. Epub 2015 Jul 15.

Authors

Allan Bastos Lima¹, Mira A M Behnam¹, Yasmin El Sherif¹, Christoph Nitsche¹, Sergio M Vechi², Christian D Klein³

Affiliations

¹ Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology IPMB, Heidelberg University, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany.
² Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology IPMB, Heidelberg University, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany; Federal University of Alagoas (UFAL), Campus Arapiraca, NCEx, 57309-005 Arapiraca, Alagoas, Brazil.
³ Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology IPMB, Heidelberg University, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany. Electronic address: c.klein@uni-heidelberg.de.

PMID: 26233795
DOI: 10.1016/j.bmc.2015.07.012

Abstract

Dengue virus (DENV) and West Nile virus (WNV) are mosquito-borne arboviruses responsible for causing acute systemic diseases and severe health conditions in humans. The discovery of therapies capable to prevent infections or treat infected individuals remains an important challenge, since no vaccine or specific efficient treatment could be developed so far. In this context, we present herein the synthesis, characterization, biological evaluation and docking studies of novel peptide-hybrids based on 2,4-thiazolidinedione scaffolds containing non-polar groups. The most promising compound has an IC50 of 0.75 μM against WNV protease, which represents a seventyfold improvement in activity compared to our previously reported compounds. Experimental results and docking studies are in agreement with the hypothesis that a non-polar group in the scaffold is important to obtain interactions between the inhibitors and a hydrophobic pocket in the substrate recognition region of the DENV and WNV NS2B-NS3 serine proteases.

Keywords: Dengue virus; Peptide-hybrids; Protease inhibitors; West Nile virus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dengue Virus / drug effects*
Humans
Models, Molecular
Peptide Hydrolases / metabolism*
Protease Inhibitors / administration & dosage
Protease Inhibitors / pharmacology
Protease Inhibitors / therapeutic use*
Viral Nonstructural Proteins / antagonists & inhibitors*
West Nile virus / drug effects*

Substances

Protease Inhibitors
Viral Nonstructural Proteins
Peptide Hydrolases