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Design, Discovery and Development of Modulators Targeting Protein-Protein Interactions
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Design, Discovery and Development of Modulators Targeting Protein-Protein Interactions

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (10 April 2023) | Viewed by 10615

Special Issue Editor

Dr. Konstantinos Agrios

E-Mail Website
Guest Editor
Department of Chemistry, Villanova University, Villanova, PA 19085, USA
Interests: drug discovery; complement therapeutics; factor D inhibition; CNS; metabolic diseases; oncology; infectious diseases

Special Issue Information

Dear Colleagues,

The human proteome comprises approximately 20,000 proteins, and protein–protein interactions (PPIs) play pivotal roles in biological processes. Their dysregulation often results in the onset and progression of several diseases. Therefore, PPIs represent promising drug discovery targets. Historically, PPIs were considered to be “undruggable” with their large and flat binding surfaces being smooth and lacking well-defined binding pockets. Targeting these is a challenging task when attempting to convert drug-like small molecules to therapeutics due to the fact that PPI interfaces exhibit different biochemical and biophysical properties relative to the small molecule compound binding pockets. Natural products, derivatives thereof, peptides, and peptidomimetics represent other sources for the modulation of PPIs. We invite authors to submit original research and review articles regarding the molecular aspects, including, but not limited to, the following topics:

— Some examples of targeted PPIs:

  • Bcl-2 family PPIs (cancer)
  • p53–MDM2 (cancer)
  • RKIP(Raf kinase inhibitory protein)—C-Raf(Raf-1 kinase) (cancer and Alzheimer’s disease)
  • Keap1–Nrf2 (cancer)

— The goal of the issue is to highlight:

  • Recent advances in understanding and mastering PPIs as drug discovery targets;
  • Targeting PPIs with:
  1. Small molecules;
  2. Peptides and peptidomimetics;
  • Natural products and derivatives thereof.

Dr. Konstantinos Agrios
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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 (PPIs)
  • drug discovery targets
  • small molecules to therapeutics
  • natural products
  • derivatives thereof
  • peptides and peptidomimetics
  • RKIP
  • Raf-1 kinase
  • Keap1–Nrf2

Published Papers (6 papers)

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Research

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22 pages, 12126 KiB  
Article
Design, Pharmacological Characterization, and Molecular Docking of Minimalist Peptidomimetic Antagonists of α4β1 Integrin
by Monica Baiula, Michele Anselmi, Francesco Musiani, Alessia Ghidini, Jacopo Carbone, Alberto Caligiana, Andrea Maurizio, Santi Spampinato and Luca Gentilucci
Int. J. Mol. Sci. 2023, 24(11), 9588; https://doi.org/10.3390/ijms24119588 - 31 May 2023
Cited by 1 | Viewed by 1348
Abstract
Integrin receptors mediate cell–cell interactions via the recognition of cell-adhesion glycoproteins, as well as via the interactions of cells with proteins of the extracellular matrix, and upon activation they transduce signals bi-directionally across the cell membrane. In the case of injury, infection, or [...] Read more.
Integrin receptors mediate cell–cell interactions via the recognition of cell-adhesion glycoproteins, as well as via the interactions of cells with proteins of the extracellular matrix, and upon activation they transduce signals bi-directionally across the cell membrane. In the case of injury, infection, or inflammation, integrins of β2 and α4 families participate in the recruitment of leukocytes, a multi-step process initiated by the capturing of rolling leukocytes and terminated by their extravasation. In particular, α4β1 integrin is deeply involved in leukocyte firm adhesion preceding extravasation. Besides its well-known role in inflammatory diseases, α4β1 integrin is also involved in cancer, being expressed in various tumors and showing an important role in cancer formation and spreading. Hence, targeting this integrin represents an opportunity for the treatment of inflammatory disorders, some autoimmune diseases, and cancer. In this context, taking inspiration from the recognition motives of α4β1 integrin with its natural ligands FN and VCAM-1, we designed minimalist α/β hybrid peptide ligands, with our approach being associated with a retro strategy. These modifications are expected to improve the compounds’ stability and bioavailability. As it turned out, some of the ligands were found to be antagonists, being able to inhibit the adhesion of integrin-expressing cells to plates coated with the natural ligands without inducing any conformational switch and any activation of intracellular signaling pathways. An original model structure of the receptor was generated using protein–protein docking to evaluate the bioactive conformations of the antagonists via molecular docking. Since the experimental structure of α4β1 integrin is still unknown, the simulations might also shed light on the interactions between the receptor and its native protein ligands. Full article
(This article belongs to the Special Issue Design, Discovery and Development of Modulators Targeting Protein-Protein Interactions)
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10 pages, 1575 KiB  
Article
Molecular Recognition of Methacryllysine and Crotonyllysine by the AF9 YEATS Domain
by Nurgül Bilgin, Laust Moesgaard, Mohammad M. Rahman, Vildan A. Türkmen, Jacob Kongsted and Jasmin Mecinović
Int. J. Mol. Sci. 2023, 24(8), 7002; https://doi.org/10.3390/ijms24087002 - 10 Apr 2023
Cited by 4 | Viewed by 1628
Abstract
Histone lysine methacrylation and crotonylation are epigenetic marks that play important roles in human gene regulation. Here, we explore the molecular recognition of histone H3 peptides possessing methacryllysine and crotonyllysine at positions 18 and 9 (H3K18 and H3K9) by the AF9 YEATS domain. [...] Read more.
Histone lysine methacrylation and crotonylation are epigenetic marks that play important roles in human gene regulation. Here, we explore the molecular recognition of histone H3 peptides possessing methacryllysine and crotonyllysine at positions 18 and 9 (H3K18 and H3K9) by the AF9 YEATS domain. Our binding studies demonstrate that the AF9 YEATS domain displays a higher binding affinity for histones possessing crotonyllysine than the isomeric methacryllysine, indicating that AF9 YEATS distinguishes between the two regioisomers. Molecular dynamics simulations reveal that the crotonyllysine/methacryllysine-mediated desolvation of the AF9 YEATS domain provides an important contribution to the recognition of both epigenetic marks. These results provide important knowledge for the development of AF9 YEATS inhibitors, an area of biomedical interest. Full article
(This article belongs to the Special Issue Design, Discovery and Development of Modulators Targeting Protein-Protein Interactions)
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19 pages, 18066 KiB  
Article
Dimeric Ankyrin with Inverted Module Promotes Bifunctional Property in Capturing Capsid to Impede HIV-1 Replication
by On-anong Juntit, Kanokporn Sornsuwan, Tanchanok Wisitponchai, Vannajan Sanghiran Lee, Supachai Sakkhachornphop, Umpa Yasamut and Chatchai Tayapiwatana
Int. J. Mol. Sci. 2023, 24(6), 5266; https://doi.org/10.3390/ijms24065266 - 09 Mar 2023
Viewed by 993
Abstract
Several anti-HIV scaffolds have been proposed as complementary treatments to highly active antiretroviral therapy. AnkGAG1D4, a designed ankyrin repeat protein, formerly demonstrated anti-HIV-1 replication by interfering with HIV-1 Gag polymerization. However, the improvement of the effectiveness was considered. Recently, the dimeric [...] Read more.
Several anti-HIV scaffolds have been proposed as complementary treatments to highly active antiretroviral therapy. AnkGAG1D4, a designed ankyrin repeat protein, formerly demonstrated anti-HIV-1 replication by interfering with HIV-1 Gag polymerization. However, the improvement of the effectiveness was considered. Recently, the dimeric molecules of AnkGAG1D4 were accomplished in enhancing the binding activity against HIV-1 capsid (CAp24). In this study, the interaction of CAp24 against the dimer conformations was elucidated to elaborate the bifunctional property. The accessibility of the ankyrin binding domains was inspected by bio-layer interferometry. By inverting the second module of dimeric ankyrin (AnkGAG1D4NC-CN), the CAp24 interaction KD was significantly reduced. This reflects the capability of AnkGAG1D4NC-CN in simultaneously capturing CAp24. On the contrary, the binding activity of dimeric AnkGAG1D4NC-NC was indistinguishable from the monomeric AnkGAG1D4. The bifunctional property of AnkGAG1D4NC-CN was subsequently confirmed in the secondary reaction with additional p17p24. This data correlates with the MD simulation, which suggested the flexibility of the AnkGAG1D4NC-CN structure. The CAp24 capturing capacity was influenced by the distance of the AnkGAG1D4 binding domains to introduce the avidity mode of AnkGAG1D4NC-CN. Consequently, AnkGAG1D4NC-CN showed superior potency in interfering with HIV-1 NL4-3 WT and HIV-1 NL4-3 MIRCAI201V replication than AnkGAG1D4NC-NC and an affinity improved AnkGAG1D4-S45Y. Full article
(This article belongs to the Special Issue Design, Discovery and Development of Modulators Targeting Protein-Protein Interactions)
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12 pages, 4787 KiB  
Communication
Transcriptome Sequencing Reveals the Mechanism behind Chemically Induced Oral Mucositis in a 3D Cell Culture Model
by Maria Lambros, Jonathan Moreno, Qinqin Fei, Cyrus Parsa, Robert Orlando and Lindsey Van Haute
Int. J. Mol. Sci. 2023, 24(5), 5058; https://doi.org/10.3390/ijms24055058 - 06 Mar 2023
Viewed by 1685
Abstract
Oral mucositis is a common side effect of cancer treatment, and in particular of treatment with the mTORC1 inhibitor everolimus. Current treatment methods are not efficient enough and a better understanding of the causes and mechanisms behind oral mucositis is necessary to find [...] Read more.
Oral mucositis is a common side effect of cancer treatment, and in particular of treatment with the mTORC1 inhibitor everolimus. Current treatment methods are not efficient enough and a better understanding of the causes and mechanisms behind oral mucositis is necessary to find potential therapeutic targets. Here, we treated an organotypic 3D oral mucosal tissue model consisting of human keratinocytes grown on top of human fibroblasts with a high or low dose of everolimus for 40 or 60 h and investigated (1) the effect of everolimus on microscopic sections of the 3D cell culture for evidence of morphologic changes and (2) changes in the transcriptome by high throughput RNA-Seq analysis. We show that the most affected pathways are cornification, cytokine expression, glycolysis, and cell proliferation and we provide further details. This study provides a good resource towards a better understanding of the development of oral mucositis. It gives a detailed overview of the different molecular pathways that are involved in mucositis. This in turn provides information about potential therapeutic targets, which is an important step towards preventing or managing this common side effect of cancer treatment. Full article
(This article belongs to the Special Issue Design, Discovery and Development of Modulators Targeting Protein-Protein Interactions)
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13 pages, 8073 KiB  
Article
Molecular and Physiological Functions of PACAP in Sweat Secretion
by Michio Yamashita, Junko Shibato, Randeep Rakwal, Naoko Nonaka, Takahiro Hirabayashi, Brian J. Harvey, Seiji Shioda and Fumiko Takenoya
Int. J. Mol. Sci. 2023, 24(5), 4572; https://doi.org/10.3390/ijms24054572 - 26 Feb 2023
Viewed by 1788
Abstract
Sweat plays a critical role in human body, including thermoregulation and the maintenance of the skin environment and health. Hyperhidrosis and anhidrosis are caused by abnormalities in sweat secretion, resulting in severe skin conditions (pruritus and erythema). Bioactive peptide and pituitary adenylate cyclase-activating [...] Read more.
Sweat plays a critical role in human body, including thermoregulation and the maintenance of the skin environment and health. Hyperhidrosis and anhidrosis are caused by abnormalities in sweat secretion, resulting in severe skin conditions (pruritus and erythema). Bioactive peptide and pituitary adenylate cyclase-activating polypeptide (PACAP) was isolated and identified to activate adenylate cyclase in pituitary cells. Recently, it was reported that PACAP increases sweat secretion via PAC1R in mice and promotes the translocation of AQP5 to the cell membrane through increasing intracellular [Ca2+] via PAC1R in NCL-SG3 cells. However, intracellular signaling mechanisms by PACAP are poorly clarified. Here, we used PAC1R knockout (KO) mice and wild-type (WT) mice to observe changes in AQP5 localization and gene expression in sweat glands by PACAP treatment. Immunohistochemistry revealed that PACAP promoted the translocation of AQP5 to the lumen side in the eccrine gland via PAC1R. Furthermore, PACAP up-regulated the expression of genes (Ptgs2, Kcnn2, Cacna1s) involved in sweat secretion in WT mice. Moreover, PACAP treatment was found to down-regulate the Chrna1 gene expression in PAC1R KO mice. These genes were found to be involved in multiple pathways related to sweating. Our data provide a solid basis for future research initiatives in order to develop new therapies to treat sweating disorders. Full article
(This article belongs to the Special Issue Design, Discovery and Development of Modulators Targeting Protein-Protein Interactions)
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Review

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21 pages, 13105 KiB  
Review
Selected Approaches to Disrupting Protein–Protein Interactions within the MAPK/RAS Pathway
by Stephen J. Harwood, Christopher R. Smith, J. David Lawson and John M. Ketcham
Int. J. Mol. Sci. 2023, 24(8), 7373; https://doi.org/10.3390/ijms24087373 - 17 Apr 2023
Cited by 3 | Viewed by 2557
Abstract
Within the MAPK/RAS pathway, there exists a plethora of protein–protein interactions (PPIs). For many years, scientists have focused efforts on drugging KRAS and its effectors in hopes to provide much needed therapies for patients with KRAS-mutant driven cancers. In this review, we [...] Read more.
Within the MAPK/RAS pathway, there exists a plethora of protein–protein interactions (PPIs). For many years, scientists have focused efforts on drugging KRAS and its effectors in hopes to provide much needed therapies for patients with KRAS-mutant driven cancers. In this review, we focus on recent strategies to inhibit RAS-signaling via disrupting PPIs associated with SOS1, RAF, PDEδ, Grb2, and RAS. Full article
(This article belongs to the Special Issue Design, Discovery and Development of Modulators Targeting Protein-Protein Interactions)
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