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Molecules
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Small Molecules Targeting Protein-Protein Interactions
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Small Molecules Targeting Protein-Protein Interactions

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 17089

Special Issue Editor

Prof. Dr. Philippe Cotelle

E-Mail Website
Guest Editor
Lille Neuroscience and Cognition, Team “Brain Biology and Chemistry”, Faculty of Pharmacy, University of Lille, Pr Laguesse street, 3 - BP83, 59006 Lille, France
Interests: enzymatic inhibition; PPI modulation; drug design; natural polyphenols; metal ligands; proliferation/apoptosis

Special Issue Information

Dear Colleagues,

Protein–protein interactions (PPIs) are physical contacts established between proteins (one of them can be an intrinsically disordered protein) as a result of biochemical events. PPI interfaces exhibit both shape and electrostatic complementarity. The protein–protein interaction (PPI) target class is particularly challenging, but may offer potential for “first in class” therapies. There are many examples of targeting protein–protein interactions in the field of cancer therapy (BCl-2/, PD-1/PDL-1, YAP or TAZ/TEAD, BET/acetylated histones, MDM2/p53), as well as in virology (LEDGF/HIV-1 integrase, CCR5/gp120). This Special Issue welcomes all contributions on screening strategies and SAR optimization of orthosteric or allosteric inhibitors on established or emerging targets. 

Prof. Philippe Cotelle
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • protein–protein interfaces
  • orthosteric inhibition
  • allosteric modulation
  • cryptic sites
  • small molecules

Published Papers (4 papers)

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Research

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12 pages, 1484 KiB  
Article
Phage-Display Based Discovery and Characterization of Peptide Ligands against WDR5
by Jiawen Cao, Tiantian Fan, Yanlian Li, Zhiyan Du, Lin Chen, Ying Wang, Xin Wang, Jingkang Shen, Xun Huang, Bing Xiong and Danyan Cao
Molecules 2021, 26(5), 1225; https://doi.org/10.3390/molecules26051225 - 25 Feb 2021
Cited by 4 | Viewed by 2490
Abstract
WD40 is a ubiquitous domain presented in at least 361 human proteins and acts as scaffold to form protein complexes. Among them, WDR5 protein is an important mediator in several protein complexes to exert its functions in histone modification and chromatin remodeling. Therefore, [...] Read more.
WD40 is a ubiquitous domain presented in at least 361 human proteins and acts as scaffold to form protein complexes. Among them, WDR5 protein is an important mediator in several protein complexes to exert its functions in histone modification and chromatin remodeling. Therefore, it was considered as a promising epigenetic target involving in anti-cancer drug development. In view of the protein–protein interaction nature of WDR5, we initialized a campaign to discover new peptide-mimic inhibitors of WDR5. In current study, we utilized the phage display technique and screened with a disulfide-based cyclic peptide phage library. Five rounds of biopanning were performed and isolated clones were sequenced. By analyzing the sequences, total five peptides were synthesized for binding assay. The four peptides are shown to have the moderate binding affinity. Finally, the detailed binding interactions were revealed by solving a WDR5-peptide cocrystal structure. Full article
(This article belongs to the Special Issue Small Molecules Targeting Protein-Protein Interactions)
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28 pages, 7416 KiB  
Article
Bidirectional Modulation of the Voltage-Gated Sodium (Nav1.6) Channel by Rationally Designed Peptidomimetics
by Nolan M. Dvorak, Paul A. Wadsworth, Pingyuan Wang, Haiying Chen, Jia Zhou and Fernanda Laezza
Molecules 2020, 25(15), 3365; https://doi.org/10.3390/molecules25153365 - 24 Jul 2020
Cited by 8 | Viewed by 3513
Abstract
Disruption of protein:protein interactions (PPIs) that regulate the function of voltage-gated Na+ (Nav) channels leads to neural circuitry aberrations that have been implicated in numerous channelopathies. One example of this pathophysiology is mediated by dysfunction of the PPI between Nav1.6 and its [...] Read more.
Disruption of protein:protein interactions (PPIs) that regulate the function of voltage-gated Na+ (Nav) channels leads to neural circuitry aberrations that have been implicated in numerous channelopathies. One example of this pathophysiology is mediated by dysfunction of the PPI between Nav1.6 and its regulatory protein fibroblast growth factor 14 (FGF14). Thus, peptides derived from FGF14 might exert modulatory actions on the FGF14:Nav1.6 complex that are functionally relevant. The tetrapeptide Glu-Tyr-Tyr-Val (EYYV) mimics surface residues of FGF14 at the β8–β9 loop, a structural region previously implicated in its binding to Nav1.6. Here, peptidomimetics derived from EYYV (6) were designed, synthesized, and pharmacologically evaluated to develop probes with improved potency. Addition of hydrophobic protective groups to 6 and truncation to a tripeptide (12) produced a potent inhibitor of FGF14:Nav1.6 complex assembly. Conversely, addition of hydrophobic protective groups to 6 followed by addition of an N-terminal benzoyl substituent (19) produced a potentiator of FGF14:Nav1.6 complex assembly. Subsequent functional evaluation using whole-cell patch-clamp electrophysiology confirmed their inverse activities, with 12 and 19 reducing and increasing Nav1.6-mediated transient current densities, respectively. Overall, we have identified a negative and positive allosteric modulator of Nav1.6, both of which could serve as scaffolds for the development of target-selective neurotherapeutics. Full article
(This article belongs to the Special Issue Small Molecules Targeting Protein-Protein Interactions)
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Review

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17 pages, 5200 KiB  
Review
Protein-Protein Interaction Disruptors of the YAP/TAZ-TEAD Transcriptional Complex
by Ajaybabu V. Pobbati and Brian P. Rubin
Molecules 2020, 25(24), 6001; https://doi.org/10.3390/molecules25246001 - 18 Dec 2020
Cited by 29 | Viewed by 5694
Abstract
The identification of protein-protein interaction disruptors (PPIDs) that disrupt the YAP/TAZ-TEAD interaction has gained considerable momentum. Several studies have shown that YAP/TAZ are no longer oncogenic when their interaction with the TEAD family of transcription factors is disrupted. The transcriptional co-regulator YAP (its [...] Read more.
The identification of protein-protein interaction disruptors (PPIDs) that disrupt the YAP/TAZ-TEAD interaction has gained considerable momentum. Several studies have shown that YAP/TAZ are no longer oncogenic when their interaction with the TEAD family of transcription factors is disrupted. The transcriptional co-regulator YAP (its homolog TAZ) interact with the surface pockets of TEADs. Peptidomimetic modalities like cystine-dense peptides and YAP cyclic and linear peptides exploit surface pockets (interface 2 and interface 3) on TEADs and function as PPIDs. The TEAD surface might pose a challenge for generating an effective small molecule PPID. Interestingly, TEADs also have a central pocket that is distinct from the surface pockets, and which small molecules leverage exclusively to disrupt the YAP/TAZ-TEAD interaction (allosteric PPIDs). Although small molecules that occupy the central pocket belong to diverse classes, they display certain common features. They are flexible, which allows them to adopt a palmitate-like conformation, and they have a predominant hydrophobic portion that contacts several hydrophobic residues and a small hydrophilic portion that faces the central pocket opening. Despite such progress, more selective PPIDs that also display favorable pharmacokinetic properties and show tolerable toxicity profiles are required to evaluate the feasibility of using these PPIDs for cancer therapy. Full article
(This article belongs to the Special Issue Small Molecules Targeting Protein-Protein Interactions)
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17 pages, 4007 KiB  
Review
Recent Small-Molecule Inhibitors of the p53–MDM2 Protein–Protein Interaction
by Anastasia Beloglazkina, Nikolai Zyk, Alexander Majouga and Elena Beloglazkina
Molecules 2020, 25(5), 1211; https://doi.org/10.3390/molecules25051211 - 07 Mar 2020
Cited by 32 | Viewed by 4968
Abstract
This review presents the last decade of studies on the synthesis of various types of small-molecule inhibitors of the p53– Mouse double minute 2 homolog (MDM2) protein–protein interaction. The main focus is placed on synthetic approaches to such molecules, their cytotoxicity, and MDM2 [...] Read more.
This review presents the last decade of studies on the synthesis of various types of small-molecule inhibitors of the p53– Mouse double minute 2 homolog (MDM2) protein–protein interaction. The main focus is placed on synthetic approaches to such molecules, their cytotoxicity, and MDM2 binding characteristics. Full article
(This article belongs to the Special Issue Small Molecules Targeting Protein-Protein Interactions)
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