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Cited by 899Protein Degradation and InhibitorsChemical Synthesis and AnalysisComputational Drug Discovery Methods

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Recent advances in the development of protein–protein interactions modulators: mechanisms and clinical trials

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Lu, Haiying, Zhou, Qiaodan, He, Jun, Jiang, Zhongliang, Peng, Cheng, Tong, Rongsheng, Shi, Jianyou·2020·Signal Transduction and Targeted Therapy
DOI 10.1038/s41392-020-00315-3PMC PMC7511340
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Abstract

Protein–protein interactions (PPIs) have pivotal roles in life processes. The studies showed that aberrant PPIs are associated with various diseases, including cancer, infectious diseases, and neurodegenerative diseases. Therefore, targeting PPIs is a direction in treating diseases and an essential strategy for the development of new drugs. In the past few decades, the modulation of PPIs has been recognized as one of the most challenging drug discovery tasks. In recent years, some PPIs modulators have entered clinical studies, some of which been approved for marketing, indicating that the modulators targeting PPIs have broad prospects. Here, we summarize the recent advances in PPIs modulators, including small molecules, peptides, and antibodies, hoping to provide some guidance to the design of novel drugs targeting PPIs in the future.

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Figures

Fig. 1 Orthosteric and allosteric mechanisms for PPI inhibition and stabilization
Fig. 1 Orthosteric and allosteric mechanisms for PPI inhibition and stabilizationCC BY · PubMed Central
Fig. 2 The p53/MDM2 interactions and inhibitors. a The p53/MDM2 signaling pathway: MDM2 directly binds to p53 and inhibits its transcriptional activity, causes ubiquitination and proteasomal degradation of p53, and exports p53 out of the nucleus which promotes p53 degradation. b MDM2 (surface)-p53 peptide (green) complex (PDB:1T4F). c The chemical structures of inhibitors of MDM2/p53
Fig. 2 The p53/MDM2 interactions and inhibitors. a The p53/MDM2 signaling pathway: MDM2 directly binds to p53 and inhibits its transcriptional activity, causes ubiquitination and proteasomal degradation of p53, and exports p53 out of the nucleus which promotes p53 degradation. b MDM2 (surface)-p53 peptide (green) complex (PDB:1T4F). c The chemical structures of inhibitors of MDM2/p53CC BY · PubMed Central
Fig. 3 The Bcl-2/Bax interactions and inhibitors. a The Bcl-2 family can be classified into two categories: the anti-apoptosis proteins and pro-apoptosis proteins. The pro-apoptosis proteins can be divided into multi-BH proteins and BH3-only proteins. b The crystal structure of Bcl-2 in complex with Bax BH3 peptide (PDB:2XA0). c The binding modes of ABT-199 binds to Bcl-2 (PDB:6GL8). d The chemical structures of inhibitors of Bcl-2/Bax
Fig. 3 The Bcl-2/Bax interactions and inhibitors. a The Bcl-2 family can be classified into two categories: the anti-apoptosis proteins and pro-apoptosis proteins. The pro-apoptosis proteins can be divided into multi-BH proteins and BH3-only proteins. b The crystal structure of Bcl-2 in complex with Bax BH3 peptide (PDB:2XA0). c The binding modes of ABT-199 binds to Bcl-2 (PDB:6GL8). d The chemical structures of inhibitors of Bcl-2/BaxCC BY · PubMed Central
Fig. 4 The XIAP/caspase-9 interactions and inhibitors. a The apoptotic pathway. There are two apoptotic pathways: extrinsic and intrinsic. The extrinsic pathway (also known as death receptor) involves the binding of a death receptor ligand to a member of the death receptor family. Active caspase-8 cleaves and activates the executioner caspase-3 and caspase-7, leading to the cell death. The intrinsic pathway (also known as mitochondrial) is mediated by caspase-9. After the mitochondrial membrane is stimulated by apoptosis, it releases cytochrome c and Smac proteins into the cytoplasm. Smac is a pro-apoptotic protein. Cytochrome c combines with Apaf-1 to form a polymer, and promotes pro-caspase-9 to form apoptotic bodies, and then activate caspase-9. The activated caspase-9 can activate other caspases, such as caspase-3, so as to induce apoptosis. b The chemical structures of inhibitors of XIAP/caspas-9
Fig. 4 The XIAP/caspase-9 interactions and inhibitors. a The apoptotic pathway. There are two apoptotic pathways: extrinsic and intrinsic. The extrinsic pathway (also known as death receptor) involves the binding of a death receptor ligand to a member of the death receptor family. Active caspase-8 cleaves and activates the executioner caspase-3 and caspase-7, leading to the cell death. The intrinsic pathway (also known as mitochondrial) is mediated by caspase-9. After the mitochondrial membrane is stimulated by apoptosis, it releases cytochrome c and Smac proteins into the cytoplasm. Smac is a pro-apoptotic protein. Cytochrome c combines with Apaf-1 to form a polymer, and promotes pro-caspase-9 to form apoptotic bodies, and then activate caspase-9. The activated caspase-9 can activate other caspases, such as caspase-3, so as to induce apoptosis. b The chemical structures of inhibitors of XIAP/caspas-9CC BY · PubMed Central
Fig. 5 The Hsp90/Cdc37 interactions and inhibitors. a Co-chaperone regulation of client protein activation. In the chaperone cycle of Hsp90, the open state Hsp90 firstly combined with HOP through its C terminal. Subsequently, it recruits Hsp40, Hsp70, client protein, and Cdc37 to form a mature complex. After ATP hydrolysis, ADP and mature client protein are released. Hsp90 is converted into an open state and enters the next ATP cycle. b The complex structure DCZ3112 and the N-terminal domain of Hsp90 modeled by molecular docking based on the crystal structure of Hsp90–Cdc37 complex (PDB:2K5B). c The chemical structures of inhibitors of Hsp90/Cdc37
Fig. 5 The Hsp90/Cdc37 interactions and inhibitors. a Co-chaperone regulation of client protein activation. In the chaperone cycle of Hsp90, the open state Hsp90 firstly combined with HOP through its C terminal. Subsequently, it recruits Hsp40, Hsp70, client protein, and Cdc37 to form a mature complex. After ATP hydrolysis, ADP and mature client protein are released. Hsp90 is converted into an open state and enters the next ATP cycle. b The complex structure DCZ3112 and the N-terminal domain of Hsp90 modeled by molecular docking based on the crystal structure of Hsp90–Cdc37 complex (PDB:2K5B). c The chemical structures of inhibitors of Hsp90/Cdc37CC BY · PubMed Central
Fig. 6 The chemical structures of inhibitors of c-Myc/Max
Fig. 6 The chemical structures of inhibitors of c-Myc/MaxCC BY · PubMed Central
Fig. 7 The KRAS/PDEδ interactions and inhibitors. a The process of KRAS localization to the plasma membrane. b The chemical structures of inhibitors of KRAS/PDEδ
Fig. 7 The KRAS/PDEδ interactions and inhibitors. a The process of KRAS localization to the plasma membrane. b The chemical structures of inhibitors of KRAS/PDEδCC BY · PubMed Central
Fig. 8 The CD40/CD40L interactions and inhibitors. a CD40/CD40L signal transduction and cellular response. After interacting with CD40L, CD40 recruits and interacts with tumor necrosis factor receptor-associated factor (TRAF) proteins. The activation of CD40-CD40L axis results in cellular events. b The chemical structures of inhibitors of CD40/CD40L
Fig. 8 The CD40/CD40L interactions and inhibitors. a CD40/CD40L signal transduction and cellular response. After interacting with CD40L, CD40 recruits and interacts with tumor necrosis factor receptor-associated factor (TRAF) proteins. The activation of CD40-CD40L axis results in cellular events. b The chemical structures of inhibitors of CD40/CD40LCC BY · PubMed Central
Fig. 9 The Skp2/Skp1 interactions and inhibitors. a The composition of Skp2–SCF complex. Cullin 1 (Cul1) forms the backbones of ubiquitin ligase complexes. Cul1 is activated by covalent conjugation with NEDD8. The SCF complex consists of the invariable components Rbx1 (RING-finger protein), Cul1 (scaffold protein), and Skp1 (adaptor protein) as well as a variable F-box-protein component, which is responsible for substrate recognition. Skp2 is a member of the F-box protein and is a substrate recognition subunit of the SCF complex. Skp2 can specifically recognize the substrate and mediate its ubiquitination degradation. b The potential-binding pockets on the interface of Skp2–Skp1 complex (PDB:1FQV). c The chemical structures of inhibitors of Skp2/Skp1
Fig. 9 The Skp2/Skp1 interactions and inhibitors. a The composition of Skp2–SCF complex. Cullin 1 (Cul1) forms the backbones of ubiquitin ligase complexes. Cul1 is activated by covalent conjugation with NEDD8. The SCF complex consists of the invariable components Rbx1 (RING-finger protein), Cul1 (scaffold protein), and Skp1 (adaptor protein) as well as a variable F-box-protein component, which is responsible for substrate recognition. Skp2 is a member of the F-box protein and is a substrate recognition subunit of the SCF complex. Skp2 can specifically recognize the substrate and mediate its ubiquitination degradation. b The potential-binding pockets on the interface of Skp2–Skp1 complex (PDB:1FQV). c The chemical structures of inhibitors of Skp2/Skp1CC BY · PubMed Central
Fig. 10 The Keap1/Nrf2 interactions and interactions. a The Keap1–Nrf2-ARE pathway. Under basal conditions, Nrf2 binds to Keap1 and is degraded by proteasomes. Under oxidative stress, Nrf2 escapes the degradation mediated by Keap1 and transfers to nucleus, binding with ARE and Maf protein to initiate the transcription of antioxidative and cytoprotective genes. b The chemical structures of inhibitors of Keap1/Nrf2
Fig. 10 The Keap1/Nrf2 interactions and interactions. a The Keap1–Nrf2-ARE pathway. Under basal conditions, Nrf2 binds to Keap1 and is degraded by proteasomes. Under oxidative stress, Nrf2 escapes the degradation mediated by Keap1 and transfers to nucleus, binding with ARE and Maf protein to initiate the transcription of antioxidative and cytoprotective genes. b The chemical structures of inhibitors of Keap1/Nrf2CC BY · PubMed Central
Fig. 11 The PD-1/PD-L1 interactions and inhibitors. a PD-1/PD-L1 signaling pathway. PD-1/PD-L1 interaction causes the phosphorylation of ITIMs and ITSMs in the intracellular domain of PD-1, and then recruits SHP2 to suppress PI3K/Akt, Ras/MAPK/ERK signaling pathway, leading to T-cell exhaustion. b The chemical structures of inhibitors of PD-1/PD-L1
Fig. 11 The PD-1/PD-L1 interactions and inhibitors. a PD-1/PD-L1 signaling pathway. PD-1/PD-L1 interaction causes the phosphorylation of ITIMs and ITSMs in the intracellular domain of PD-1, and then recruits SHP2 to suppress PI3K/Akt, Ras/MAPK/ERK signaling pathway, leading to T-cell exhaustion. b The chemical structures of inhibitors of PD-1/PD-L1CC BY · PubMed Central
Fig. 12 The chemical structures of stabilizers of 14-3-3
Fig. 12 The chemical structures of stabilizers of 14-3-3CC BY · PubMed Central
Fig. 13 Proteins and small molecule inhibitors of S100 pentamer. a The binding modes of trifluoroperazine binds to S100 (PDB:3KO0). Due to the clarity, only two adjacent S100A4 monomers and their contact interface are shown. b The chemical structure of a stabilizer of S100 pentamer
Fig. 13 Proteins and small molecule inhibitors of S100 pentamer. a The binding modes of trifluoroperazine binds to S100 (PDB:3KO0). Due to the clarity, only two adjacent S100A4 monomers and their contact interface are shown. b The chemical structure of a stabilizer of S100 pentamerCC BY · PubMed Central
Fig. 14 The chemical structures of stabilizers of influenza nucleoprotein
Fig. 14 The chemical structures of stabilizers of influenza nucleoproteinCC BY · PubMed Central
Fig. 15 The chemical structures of stabilizers of microtubules
Fig. 15 The chemical structures of stabilizers of microtubulesCC BY · PubMed Central

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Items 201–271 of 271

Research works printed but not linked: 3

  1. Ferrari, S., Pellati, F. & Costi, M. P. Disruption of Protein-Protein Interfaces (Springer, Berlin, 2013).
  2. Chen, L. et al. P53 alpha-helix mimetics antagonize p53/MDM2 interaction and activate p53. Mol. Cancer Therap. 4, 1019–1025 (2005). · DOI
  3. Li, X., Liu, R. & Fang, H. Bcl-2: research progress from target to launched drug. Acta Pharma. Sin. 53, 509–517 (2018).

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Metadata

Authors
Lu, H., Zhou, Q., He, J., Jiang, Z., Peng, C., Tong, R., & Shi, J.
Affiliations
  • University of Electronic Science and Technology of China (CN)
  • Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital (CN)
  • Sichuan University (CN)
  • University of Miami (US)
  • Chengdu University of Traditional Chinese Medicine (CN)
Corresponding author
  • Peng, Cheng
  • Tong, Rongsheng
  • Shi, Jianyou
ORCID
Venue
Signal Transduction and Targeted Therapy
Publisher
Springer Science and Business Media LLC
Published
2020-09-23
Volume
5
Issue
1
Pages
213-213
ISSN
2059-3635 (ISSN-L)
DOI
10.1038/s41392-020-00315-3
PMC
PMC7511340
OpenAlex
W3087769169
Cited by
891
References
272
Citations by year
2026: 125 · 2025: 195 · 2024: 192 · 2023: 159 · 2022: 141 · 2021: 75 · 2020: 1
FWCI
9.07
Type
journal article
Language
en
Open access
Licence
Locations
  • Signal Transduction and Targeted Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Chengdu Science and Technology Bureau (No. 2015-HM01-00463-SF)
  • State Administration of Traditional Chinese Medicine of the People’ Republic of China (JDZX2015210)
  • the Open Research Fund of Chengdu University of Traditional Chinese Medicine Key Laboratory of Systematic Research of Distinctive Chinese Medicine Resources in Southwest China
  • the Key Research and Development Program of Science and Technology Department of Sichuan Provinc
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
Keywords
protein-protein interaction, PPI inhibitors, drug discovery, small molecules, peptides, immunoglobulins, cancer, infectious diseases, neurodegenerative diseases, clinical trials
MeSH terms
Humans, Infections, Neoplasms, Drug Delivery Systems, Neurodegenerative Diseases, Drug Discovery, Protein Interaction Maps

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