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Design of ultrahigh-affinity and dual-specificity peptide antagonists of MDM2 and MDMX for P53 activation and tumor suppression

引用

Acta Pharmaceutica Sinica B 2021年第9期11卷 2655-2669页

作者： Xiang Li Neelakshi Gohain Si Chen Yinghua Li Xiaoyuan Zhao Bo Li William D.Tolbert Wangxiao He Marzena Pazgier Honggang Hu Wuyuan Lu School of Pharmacy Second Military Medical UniversityShanghai 200433China Institute of Human Virology and Department of Biochemistry and Molecular Biology University of Maryland School of MedicineBaltimoreMD 21201USA School of Medicine Shanghai UniversityShanghai 200444China Institute of Translational Medicine Shanghai UniversityShanghai 200444China State Key Laboratory of Rare Earth Resource Utilization Changchun Institute of Applied ChemistryChinese Academy of SciencesChangchun 130022China Department of Talent Highland the First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an 710061China Key Laboratory of Medical Molecular Virology(MOE/NHC/CAMS)of School of Basic Medical Sciences and Shanghai Institute of Infectious Disease and Biosecurity of School of Public Health Fudan UniversityShanghai 200032China

Peptide inhibition of the interactions of the tumor suppressor protein P53 with its negative regulators MDM2 and MDMX activates P53 in vitro and in vivo,representing a viable therapeutic strategy for cancer *** phage display techniques,we previously identified a potent peptide activator of P53,termed PMI(TSFAEYWNLLSP),with binding affinities for both MDM2 and MDMX in the low nanomolar concentration *** we report an ultrahigh affinity,dual-specificity peptide antagonist of MDM2 and MDMX obtained through systematic mutational analysis and additivitybased molecular *** assays of over 100 peptide analogs of PMI using surface plasmon resonance and fluorescence polarization techniques yielded a dodecameric peptide termed PMI-M3(LTFLEYWAQLMQ)that bound to MDM2 and MDMX with K_(d)values in the low picomolar concentration range as verified by isothermal titration ***-crystal structures of MDM2 and of MDMX in complex with PMI-M3 were solved at 1.65 and 3.0 A resolution,*** to PMI,PMI-M3 occupied the P53-binding pocket of MDM2/MDMX,which was dominated energetically by intermolecular interactions involving Phe3,Tyr6,Trp7,and Leu *** differences in binding between PMI-M3 and PMI were observed at other positions such as Leu4 and Met11 with MDM2,and Leu1 and Met11 with MDMX,collectively contributing to a significantly enhanced binding affinity of PMI-M3 for both *** adding lysine residues to both ends of PMI and PMI-M3 to improve their cellular uptake,we obtained modified peptides termed PMI-2K(KTSFAEYWNLLSPK)and M3-2K(KLTFLEYWAQLMQK).Compared with PMI-2K,M3-2K exhibited significantly improved antitumor activities in vitro and in vivo in a P53-dependent *** super-strong peptide inhibitor of the P53-MDM2/MDMX interactions may become,in its own right,a powerful lead compound for anticancer drug development,and can aid molecular design of other classes of P53 activators as well for anticancer therapy.

关键词： MDM2 MDMX P53 Antitumor peptide systematic mutational analysis

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