Inhibition of hepatitis C virus NS3 protease by peptides derived from complementarity-determining regions (CDRs) of the monoclonal antibody 8D4: tolerance of a CDR peptide to conformational changes of a target.
We have synthesized and characterized peptides derived from complementarity-determining regions (CDRs) of 8D4, a mouse monoclonal antibody against NS3 protease domain of hepatitis C virus. 8D4 inhibits enzymatic activity without its cofactor, NS4A peptide. One of the synthetic peptides derived from CDRs, CDR1 of the heavy-chain (CDR-H1) peptide strongly inhibited NS3 protease activity competitively in the absence of NS4A and non-competitively in the presence of NS4A. Moreover, cyclic CDR-H1 peptides bridged by disulfide inhibited NS3 protease more potently. The chain length of the CDR-H1 peptide is critical for strong inhibition, even when the peptide is circularized. This finding suggests the importance of peptide conformation. In contrast to a cognate antibody molecule, CDR-derived peptides may provide good ligands for target molecules by having a tolerance to conformational changes of the targets caused by cofactor binding or mutation.
Tsumoto
Kouhei
K
Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University, 980-8579, Sendai, Japan. tsumoto@mail.cc.tohoku.ac.jp
Misawa
Satoru
S
Ohba
Yoichi
Y
Ueno
Takamasa
T
Hayashi
Hideya
H
Kasai
Nobuhiro
N
Watanabe
Hideki
H
Asano
Ryutaro
R
Kumagai
Izumi
I
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D001667:Binding, Competitive / Q000502:physiology; D022801:Complementarity Determining Regions / Q000737:chemistry; D004789:Enzyme Activation / Q000187:drug effects; D007700:Kinetics; D008024:Ligands; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000502:physiology; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000911:Antibodies, Monoclonal; D022801:Complementarity Determining Regions; D008024:Ligands; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases