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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 (30 March 2018) | Viewed by 54870

Special Issue Editors

Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, James Black Centre, Dow Street, Dundee DD1 5EH, UK
Interests: structural and chemical biology of protein–protein interactions; chemical probe development; ubiquitin–proteasome system; targeted protein degradation (PROTACs); chromatin-reader domains; fragment-based drug discovery
Facultat de Farmàcia i Ciències de l'Alimentació, Institut de Biomedicina (IBUB), Universitat de Barcelona. Av. Joan XXIII 27–31, 08028 Barcelona, Spain
Interests: drug discovery of protein–protein interactions; fragment-based drug discovery; E3 ubiquitin ligases; computational techniques; neurodegenerative disorders; personalized medicine

Special Issue Information

Dear Colleagues,

It is indisputable that there is a need to expand the druggable genome since only a small portion of it is pharmaceutically accessible to classical drug discovery approaches. Transcription factors, scaffolding proteins, pharmacological chaperones and multi-subunit enzymes have in major part been considered no go targets. These target classes rarely present deep active sites that can bind small molecules with high affinity, and in contrast function via formation of specific protein–protein interactions (PPIs). These interactions are considered difficult, due to the often large and flat surface areas that need to be targeted. Ligandability challenges, combined with historic failures of early high-throughput screening campaigns by the pharmaceutical industry against PPI targets, rapidly contributed to perceiving PPIs as “undruggable” space.

In recent years, however, these perceptions and misconceptions about targeting protein–protein interactions are beginning to break. Dozens of drug-like small molecules and peptides that target different protein-protein interactions have entered clinical trials or even they are approved (e.g., tirofiban, Merck). Many chemical probes that intervene onto specific PPIs have been developed by industry and academia, opening tremendous new opportunities to explore biology. Targeting protein-protein interaction is, nowadays, a highly rewarding scientific endeavour, providing many opportunities to modalities of chemical intervention other than conventional inhibition, and beyond traditional Rule-of-5 compliant chemical space.

Researchers in the field of chemical biology and drug discovery of protein-protein interactions are cordially invited to contribute with original papers and reviews to this Special Issue of Molecules, which report on the design and synthesis, evaluation and development of new small molecules or peptides that target to protein–protein interactions or new computational and biophysical approaches and technologies to target protein–protein interactions.

Prof. Dr. Alessio Ciulli
Dr. Carles Galdeano
Guest Editors

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 interactions
  • Rational design: Structure-based
  • drug discovery
  • Fragment-based drug discovery
  • Computational approaches
  • Biophysical techniques
  • High-throughput screening

Published Papers (7 papers)

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Research

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21 pages, 2202 KiB  
Article
Design, Synthesis, and Evaluation of Novel Immunomodulatory Small Molecules Targeting the CD40–CD154 Costimulatory Protein-Protein Interaction
by Damir Bojadzic, Jinshui Chen, Oscar Alcazar and Peter Buchwald
Molecules 2018, 23(5), 1153; https://doi.org/10.3390/molecules23051153 - 11 May 2018
Cited by 10 | Viewed by 5580
Abstract
We report the design, synthesis, and testing of novel small-molecule compounds targeting the CD40–CD154 (CD40L) costimulatory interaction for immunomodulatory purposes. This protein-protein interaction (PPI) is a TNF-superfamily (TNFSF) costimulatory interaction that is an important therapeutic target since it plays crucial roles in the [...] Read more.
We report the design, synthesis, and testing of novel small-molecule compounds targeting the CD40–CD154 (CD40L) costimulatory interaction for immunomodulatory purposes. This protein-protein interaction (PPI) is a TNF-superfamily (TNFSF) costimulatory interaction that is an important therapeutic target since it plays crucial roles in the activation of T cell responses, and there is resurgent interest in its modulation with several biologics in development. However, this interaction, just as all other PPIs, is difficult to target by small molecules. Following up on our previous work, we have now identified novel compounds such as DRI-C21091 or DRI-C21095 that show activity (IC50) in the high nanomolar to low micromolar range in the binding inhibition assay and more than thirty-fold selectivity versus other TNFSF PPIs including OX40–OX40L, BAFFR-BAFF, and TNF-R1-TNFα. Protein thermal shift (differential scanning fluorimetry) assays indicate CD154 and not CD40 as the binding partner. Activity has also been confirmed in cell assays and in a mouse model (alloantigen-induced T cell expansion in a draining lymph node). Our results expand the chemical space of identified small-molecule CD40–CD154 costimulatory inhibitors and provide lead structures that have the potential to be developed as orally bioavailable immunomodulatory therapeutics that are safer and less immunogenic than corresponding biologics. Full article
(This article belongs to the Special Issue Protein-Protein Interactions)
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1253 KiB  
Article
Binding Direction-Based Two-Dimensional Flattened Contact Area Computing Algorithm for Protein–Protein Interactions
by Beom Sik Kang, GaneshKumar Pugalendhi and Ku-Jin Kim
Molecules 2017, 22(10), 1722; https://doi.org/10.3390/molecules22101722 - 13 Oct 2017
Cited by 2 | Viewed by 3759
Abstract
Interactions between protein molecules are essential for the assembly, function, and regulation of proteins. The contact region between two protein molecules in a protein complex is usually complementary in shape for both molecules and the area of the contact region can be used [...] Read more.
Interactions between protein molecules are essential for the assembly, function, and regulation of proteins. The contact region between two protein molecules in a protein complex is usually complementary in shape for both molecules and the area of the contact region can be used to estimate the binding strength between two molecules. Although the area is a value calculated from the three-dimensional surface, it cannot represent the three-dimensional shape of the surface. Therefore, we propose an original concept of two-dimensional contact area which provides further information such as the ruggedness of the contact region. We present a novel algorithm for calculating the binding direction between two molecules in a protein complex, and then suggest a method to compute the two-dimensional flattened area of the contact region between two molecules based on the binding direction. Full article
(This article belongs to the Special Issue Protein-Protein Interactions)
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Review

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21 pages, 1122 KiB  
Review
Bioluminescence Resonance Energy Transfer as a Method to Study Protein-Protein Interactions: Application to G Protein Coupled Receptor Biology
by Chayma El Khamlichi, Flora Reverchon-Assadi, Nadège Hervouet-Coste, Lauren Blot, Eric Reiter and Séverine Morisset-Lopez
Molecules 2019, 24(3), 537; https://doi.org/10.3390/molecules24030537 - 01 Feb 2019
Cited by 34 | Viewed by 10177
Abstract
The bioluminescence resonance energy transfer (BRET) approach involves resonance energy transfer between a light-emitting enzyme and fluorescent acceptors. The major advantage of this technique over biochemical methods is that protein-protein interactions (PPI) can be monitored without disrupting the natural environment, frequently altered by [...] Read more.
The bioluminescence resonance energy transfer (BRET) approach involves resonance energy transfer between a light-emitting enzyme and fluorescent acceptors. The major advantage of this technique over biochemical methods is that protein-protein interactions (PPI) can be monitored without disrupting the natural environment, frequently altered by detergents and membrane preparations. Thus, it is considered as one of the most versatile technique for studying molecular interactions in living cells at “physiological” expression levels. BRET analysis has been applied to study many transmembrane receptor classes including G-protein coupled receptors (GPCR). It is well established that these receptors may function as dimeric/oligomeric forms and interact with multiple effectors to transduce the signal. Therefore, they are considered as attractive targets to identify PPI modulators. In this review, we present an overview of the different BRET systems developed up to now and their relevance to identify inhibitors/modulators of protein–protein interaction. Then, we introduce the different classes of agents that have been recently developed to target PPI, and provide some examples illustrating the use of BRET-based assays to identify and characterize innovative PPI modulators in the field of GPCRs biology. Finally, we discuss the main advantages and the limits of BRET approach to characterize PPI modulators. Full article
(This article belongs to the Special Issue Protein-Protein Interactions)
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14 pages, 6142 KiB  
Review
14-3-3: A Case Study in PPI Modulation
by Alice Ballone, Federica Centorrino and Christian Ottmann
Molecules 2018, 23(6), 1386; https://doi.org/10.3390/molecules23061386 - 08 Jun 2018
Cited by 36 | Viewed by 7250
Abstract
In recent years, targeting the complex network of protein–protein interactions (PPIs) has been identified as a promising drug-discovery approach to develop new therapeutic strategies. 14-3-3 is a family of eukaryotic conserved regulatory proteins which are of high interest as potential targets for pharmacological [...] Read more.
In recent years, targeting the complex network of protein–protein interactions (PPIs) has been identified as a promising drug-discovery approach to develop new therapeutic strategies. 14-3-3 is a family of eukaryotic conserved regulatory proteins which are of high interest as potential targets for pharmacological intervention in human diseases, such as cancer and neurodegenerative and metabolic disorders. This viewpoint is built on the “hub” nature of the 14-3-3 proteins, binding to several hundred identified partners, consequently implicating them in a multitude of different cellular mechanisms. In this review, we provide an overview of the structural and biological features of 14-3-3 and the modulation of 14-3-3 PPIs for discovering small molecular inhibitors and stabilizers of 14-3-3 PPIs. Full article
(This article belongs to the Special Issue Protein-Protein Interactions)
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16 pages, 1381 KiB  
Review
Receptor–Receptor Interactions in Multiple 5-HT1A Heteroreceptor Complexes in Raphe-Hippocampal 5-HT Transmission and Their Relevance for Depression and Its Treatment
by Dasiel O. Borroto-Escuela, Manuel Narváez, Patrizia Ambrogini, Luca Ferraro, Ismel Brito, Wilber Romero-Fernandez, Yuniesky Andrade-Talavera, Antonio Flores-Burgess, Carmelo Millon, Belen Gago, Jose Angel Narvaez, Yuji Odagaki, Miklos Palkovits, Zaida Diaz-Cabiale and Kjell Fuxe
Molecules 2018, 23(6), 1341; https://doi.org/10.3390/molecules23061341 - 03 Jun 2018
Cited by 37 | Viewed by 10151
Abstract
Due to the binding to a number of proteins to the receptor protomers in receptor heteromers in the brain, the term “heteroreceptor complexes” was introduced. A number of serotonin 5-HT1A heteroreceptor complexes were recently found to be linked to the ascending 5-HT pathways [...] Read more.
Due to the binding to a number of proteins to the receptor protomers in receptor heteromers in the brain, the term “heteroreceptor complexes” was introduced. A number of serotonin 5-HT1A heteroreceptor complexes were recently found to be linked to the ascending 5-HT pathways known to have a significant role in depression. The 5-HT1A–FGFR1 heteroreceptor complexes were involved in synergistically enhancing neuroplasticity in the hippocampus and in the dorsal raphe 5-HT nerve cells. The 5-HT1A protomer significantly increased FGFR1 protomer signaling in wild-type rats. Disturbances in the 5-HT1A–FGFR1 heteroreceptor complexes in the raphe-hippocampal 5-HT system were found in a genetic rat model of depression (Flinders sensitive line (FSL) rats). Deficits in FSL rats were observed in the ability of combined FGFR1 and 5-HT1A agonist cotreatment to produce antidepressant-like effects. It may in part reflect a failure of FGFR1 treatment to uncouple the 5-HT1A postjunctional receptors and autoreceptors from the hippocampal and dorsal raphe GIRK channels, respectively. This may result in maintained inhibition of hippocampal pyramidal nerve cell and dorsal raphe 5-HT nerve cell firing. Also, 5-HT1A–5-HT2A isoreceptor complexes were recently demonstrated to exist in the hippocampus and limbic cortex. They may play a role in depression through an ability of 5-HT2A protomer signaling to inhibit the 5-HT1A protomer recognition and signaling. Finally, galanin (1–15) was reported to enhance the antidepressant effects of fluoxetine through the putative formation of GalR1–GalR2–5-HT1A heteroreceptor complexes. Taken together, these novel 5-HT1A receptor complexes offer new targets for treatment of depression. Full article
(This article belongs to the Special Issue Protein-Protein Interactions)
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14 pages, 286 KiB  
Review
Effector–Immunity Pairs Provide the T6SS Nanomachine its Offensive and Defensive Capabilities
by Xiaobing Yang, Mingxiu Long and Xihui Shen
Molecules 2018, 23(5), 1009; https://doi.org/10.3390/molecules23051009 - 26 Apr 2018
Cited by 40 | Viewed by 6711
Abstract
Type VI protein secretion systems (T6SSs) are specialized transport apparatus which can target both eukaryotic and prokaryotic cells and play key roles in host–pathogen–microbiota interactions. Therefore, T6SSs have attracted much attention as a research topic during the past ten years. In this review, [...] Read more.
Type VI protein secretion systems (T6SSs) are specialized transport apparatus which can target both eukaryotic and prokaryotic cells and play key roles in host–pathogen–microbiota interactions. Therefore, T6SSs have attracted much attention as a research topic during the past ten years. In this review, we particularly summarized the T6SS antibacterial function, which involves an interesting offensive and defensive mechanism of the effector–immunity (E–I) pairs. The three main categories of effectors that target the cell wall, membranes, and nucleic acids during bacterial interaction, along with their corresponding immunity proteins are presented. We also discuss structural analyses of several effectors and E–I pairs, which explain the offensive and defensive mechanisms underpinning T6SS function during bacterial competition for niche-space, as well as the bioinformatics, proteomics, and protein–protein interaction (PPI) methods used to identify and characterize T6SS mediated E–I pairs. Additionally, we described PPI methods for verifying E–I pairs. Full article
(This article belongs to the Special Issue Protein-Protein Interactions)
18 pages, 2805 KiB  
Review
Using Peptidomimetics and Constrained Peptides as Valuable Tools for Inhibiting Protein–Protein Interactions
by Naomi S. Robertson and David R. Spring
Molecules 2018, 23(4), 959; https://doi.org/10.3390/molecules23040959 - 19 Apr 2018
Cited by 67 | Viewed by 10125
Abstract
Protein–protein interactions (PPIs) are tremendously important for the function of many biological processes. However, because of the structure of many protein–protein interfaces (flat, featureless and relatively large), they have largely been overlooked as potential drug targets. In this review, we highlight the current [...] Read more.
Protein–protein interactions (PPIs) are tremendously important for the function of many biological processes. However, because of the structure of many protein–protein interfaces (flat, featureless and relatively large), they have largely been overlooked as potential drug targets. In this review, we highlight the current tools used to study the molecular recognition of PPIs through the use of different peptidomimetics, from small molecules and scaffolds to peptides. Then, we focus on constrained peptides, and in particular, ways to constrain α-helices through stapling using both one- and two-component techniques. Full article
(This article belongs to the Special Issue Protein-Protein Interactions)
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