title: Phenylalanine and Phenylglycine Analogues as Arginine Mimetics in Dengue Protease Inhibitors.
abstract: Dengue virus is an increasingly global pathogen. One of the promising targets for antiviral drug discovery against dengue and related flaviviruses such as West Nile virus is the viral serine protease NS2B-NS3. We here report the synthesis and in vitro characterization of potent peptidic inhibitors of dengue virus protease that incorporate phenylalanine and phenylglycine derivatives as arginine-mimicking groups with modulated basicity. The most promising compounds were (4-amidino)-L-phenylalanine-containing inhibitors, which reached nanomolar affinities against dengue virus protease. The type and position of the substituents on the phenylglycine and phenylalanine side chains has a significant effect on the inhibitory activity against dengue virus protease and selectivity against other proteases. In addition, the non-natural, basic amino acids described here may have relevance for the development of other peptidic and peptidomimetic drugs such as inhibitors of the blood clotting cascade.
authors.affiliation: Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology IPMB, Heidelberg University , Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany.
authors.forename: Lena F
authors.initials: LF
authors.lastname: Weigel
authors.affiliation: Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology IPMB, Heidelberg University , Im Neuenheimer Feld 364, D-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, D-69120 Heidelberg, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Graf
authors.affiliation: Department of Infectious Diseases, Molecular Virology, Heidelberg University , Im Neuenheimer Feld 345, D-69120 Heidelberg, Germany.|German Centre for Infection Research, Heidelberg University , D-69120 Heidelberg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Bartenschlager
authors.affiliation: Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology IPMB, Heidelberg University , Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany.
authors.forename: Christian D
authors.initials: CD
authors.lastname: Klein
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007611:Aprotinin / Q000378:metabolism / Q000494:pharmacology; D001120:Arginine / Q000737:chemistry*; D002460:Cell Line / Q000187:drug effects / Q000821:virology; D002463:Cell Membrane Permeability / Q000187:drug effects; D003716:Dengue Virus / Q000187:drug effects* / Q000472:pathogenicity; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004355:Drug Stability; D006801:Humans; D008297:Male; D062105:Molecular Docking Simulation; D018716:Molecular Mimicry; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014902:West Nile virus / Q000201:enzymology; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D007611:Aprotinin; D001120:Arginine; D010649:Phenylalanine; D011480:Protease Inhibitors; D012697:Serine Endopeptidases; C504449:NS3 protease, dengue virus; D000085242:Viral Proteases