title: C-terminal residue optimization and fragment merging: discovery of a potent Peptide-hybrid inhibitor of dengue protease.
abstract: 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, K i = 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.
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: 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: Sérgio 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.
authors.forename: Christian D
authors.initials: CD
authors.lastname: Klein
keywords: Dengue virus; fragment merging; peptide; protease inhibitor