TY - JOUR
T1 - Single-Molecule Force Measurement Guides the Design of Multivalent Ligands with Picomolar Affinity
AU - Yang, Zhen
AU - Jiang, Sheng
AU - Li, Feng
AU - Qiu, Yatao
AU - Gu, Jianhua
AU - Pettigrew, Roderic I.
AU - Ferrari, Mauro
AU - Hamilton, Dale J.
AU - Li, Zheng
N1 - Funding Information:
This work was supported by the Houston Methodist Research Institute and Foundation. Additional support was acquired from the following sources: DoD BCRP Breakthrough Award (BC141561P1) (Z.L.), Kostas Research foundation award (Z.L.), the National Institutes of Health (U54CA143837, U54CA151668, U54CA210181) (M.F.), Finger Distinguished Endowed Chair (D.H.), National Natural Science Foundation of China(81773559, 21472191)-(S.J.), China Pharmaceutical University(CPU2018GY03, CPU2018GY24, SKLNMZZRC201810) (S.J). We thank the electron microscopy and small animal imaging core facility of Houston Methodist Research Institute. Dr. Zhong Xue is acknowledged for providing algorithm calculation support.
Publisher Copyright:
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
PY - 2019/4/8
Y1 - 2019/4/8
N2 - Interaction of multiple entities and receptors, or multivalency is widely applied to achieve high affinity ligands for diagnostic and therapeutic purposes. However, lack of knowledge on receptor distribution in living subjects remains a challenge for rational structure design. Herein, we develop a force measurement platform to probe the distribution and separation of the cell surface vascular endothelial growth factor receptors (VEGFR) in live cells, and use this to assess the geometry of appropriate linkers for distinct multivalent binding modes. A tetravalent lead ZD-4, which was developed from an antitumor drug ZD6474 (Vandetanib) with combined hybrid binding effects, yielded a 2000-fold improvement in the binding affinity to VEGFR with IC 50 value of 25 pm. We confirmed the improved affinity by the associated increase of tumor uptake in the VEGFR-targeting positron emission tomography (PET) imaging using U87 tumor xenograft mouse model.
AB - Interaction of multiple entities and receptors, or multivalency is widely applied to achieve high affinity ligands for diagnostic and therapeutic purposes. However, lack of knowledge on receptor distribution in living subjects remains a challenge for rational structure design. Herein, we develop a force measurement platform to probe the distribution and separation of the cell surface vascular endothelial growth factor receptors (VEGFR) in live cells, and use this to assess the geometry of appropriate linkers for distinct multivalent binding modes. A tetravalent lead ZD-4, which was developed from an antitumor drug ZD6474 (Vandetanib) with combined hybrid binding effects, yielded a 2000-fold improvement in the binding affinity to VEGFR with IC 50 value of 25 pm. We confirmed the improved affinity by the associated increase of tumor uptake in the VEGFR-targeting positron emission tomography (PET) imaging using U87 tumor xenograft mouse model.
KW - PET imaging
KW - atomic force microscopy
KW - ligand design
KW - multivalency
KW - tumor targeting
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U2 - 10.1002/anie.201814347
DO - 10.1002/anie.201814347
M3 - Article
C2 - 30697890
AN - SCOPUS:85061913116
SN - 1433-7851
VL - 58
SP - 5272
EP - 5276
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 16
ER -