PMID- 36108586
OWN - NLM
STAT- MEDLINE
DCOM- 20240123
LR  - 20240123
IS  - 1090-2120 (Electronic)
IS  - 0045-2068 (Linking)
VI  - 129
DP  - 2022 Dec
TI  - Optimization of a cell surface vimentin binding peptoid to extract antagonist 
      effect on lung cancer cells.
PG  - 106113
LID - S0045-2068(22)00519-3 [pii]
LID - 10.1016/j.bioorg.2022.106113 [doi]
AB  - Targeting cytoskeletal proteins that are uniquely translocated to cancer cell 
      surface may provide an alternative path for conventional drug discovery. Vimentin 
      is such a cell surface-translocated cytoskeletal protein (CSV) found in non small 
      cell lung cancer (NSCLC). We previously reported the identification of 
      CSV-binding peptoid, named JM3A. While JM3A had no antagonist effect, here we 
      used multiple strategies to optimize the binding of JM3A on CSV and extract the 
      antagonistic effect. We first performed minimum pharmacophore identification 
      studies using alanine/sarcosine scans. These studies revealed that residues 1-4 
      and 8 (from the C-terminus) are not important and those residues 5-7 are 
      important for JM3A binding to CSV. We then found that our previous N-terminal 
      benzophenone (BP)-coupled JM3A (JM3A-BP), which was used for pull-down and target 
      identification studies, displayed 3-fold binding enhancement. The molecular 
      docking studies indicated that the BP moiety binds to a new binding pocket on the 
      vimentin coil 2 fragment, and further studies using 12 benzophenone-like moieties 
      indicated that at least two phenyl groups are needed to occupy this new binding 
      site. Interestingly, the binding was improved when non-important and bulky 
      residues at the 4th and 8th positions were replaced with methyl groups 
      (JM3A-4,8-BP). We next dimerized JM3A-4,8-BP to enhance the binding via the 
      "avidity effect," using a central lysine linker to develop JM3A-4,8-BPD1 
      (EC(50) = 300 nM). This showed 27- and 63-fold-improvement in binding over 
      JM3A-4,8-BP and JM3A monomers, respectively. JM3A4,8BPD1 also displayed binding 
      comparable to vimentin antibody. Finally, we observed an antagonist effect on 
      H1299 NSCLC cell proliferation and viability from this most improved dimeric 
      JM3A-4,8BPD1, which was not shown by the monomeric versions.
CI  - Copyright (c) 2022 Elsevier Inc. All rights reserved.
FAU - Zhang, Haowen
AU  - Zhang H
AD  - Department of Pharmacological & Pharmaceutical Sciences, University of 
      Houston, 4349 Martin Luther King Blvd, Health Building 2, Houston, TX 77204-5037, 
      USA.
FAU - Gomika Udugamasooriya, D
AU  - Gomika Udugamasooriya D
AD  - Department of Pharmacological & Pharmaceutical Sciences, University of 
      Houston, 4349 Martin Luther King Blvd, Health Building 2, Houston, TX 77204-5037, 
      USA; Department of Cancer Systems Imaging, MD Anderson Cancer Center, 1881 East 
      Road, Houston, TX 77030-4009, USA. Electronic address: gomika@uh.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220906
PL  - United States
TA  - Bioorg Chem
JT  - Bioorganic chemistry
JID - 1303703
RN  - 0 (Benzophenones)
RN  - 0 (Peptoids)
RN  - 0 (Vimentin)
RN  - 0 (peptoid JM3A)
SB  - IM
MH  - Humans
MH  - Benzophenones
MH  - *Carcinoma, Non-Small-Cell Lung/drug therapy
MH  - *Lung Neoplasms/drug therapy
MH  - Molecular Docking Simulation
MH  - *Peptoids/pharmacology
MH  - Vimentin/metabolism
OTO - NOTNLM
OT  - Dimerization
OT  - Lung cancer
OT  - Minimum pharmacophore
OT  - Peptoid
OT  - Vimentin
COIS- Declaration of Competing Interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2022/09/16 06:00
MHDA- 2022/11/09 06:00
CRDT- 2022/09/15 18:30
PHST- 2022/07/17 00:00 [received]
PHST- 2022/08/21 00:00 [revised]
PHST- 2022/08/23 00:00 [accepted]
PHST- 2022/09/16 06:00 [pubmed]
PHST- 2022/11/09 06:00 [medline]
PHST- 2022/09/15 18:30 [entrez]
AID - S0045-2068(22)00519-3 [pii]
AID - 10.1016/j.bioorg.2022.106113 [doi]
PST - ppublish
SO  - Bioorg Chem. 2022 Dec;129:106113. doi: 10.1016/j.bioorg.2022.106113. Epub 2022 
      Sep 6.