title: Dual inhibitors of the dengue and West Nile virus NS2B-NS3 proteases: Synthesis, biological evaluation and docking studies of novel peptide-hybrids.
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.
authors.affiliation: Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology IPMB, Heidelberg University, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany.
authors.forename: Allan
authors.initials: A
authors.lastname: Bastos Lima
authors.affiliation: Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology IPMB, Heidelberg University, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany.
authors.forename: Mira A M
authors.initials: MA
authors.lastname: Behnam
authors.affiliation: Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology IPMB, Heidelberg University, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany.
authors.forename: Yasmin
authors.initials: Y
authors.lastname: El Sherif
authors.affiliation: Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology IPMB, Heidelberg University, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Nitsche
authors.affiliation: 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.
authors.forename: Sergio M
authors.initials: SM
authors.lastname: Vechi
authors.affiliation: 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.
authors.forename: Christian D
authors.initials: CD
authors.lastname: Klein
mesh_terms: D003716:Dengue Virus / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D010447:Peptide Hydrolases / Q000378:metabolism*; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014902:West Nile virus / Q000187:drug effects*
chemical_list: D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; D010447:Peptide Hydrolases
keywords: Dengue virus; Peptide-hybrids; Protease inhibitors; West Nile virus