| The Critical Role of Protein-Protein Interactions (PPIs) |
PPIs serve as fundamental regulatory events of many cellular processes,
including signal transduction, proliferation, and apoptosis. With an estimated 650,000 PPIs in humans[1], these interactions form intricate networks that govern protein function. Dysregulated PPIs are implicated in diseases such as cancer, infections, and neurodegenerative disorders, making them promising yet challenging therapeutic targets. PPI inhibitors offer a powerful strategy to modulate these interactions, opening new avenues for drug development. |
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| Figure 1. Schematic of PPI networks[2]. |
| Why Are PPIs Challenging Drug Targets? |
| Despite their therapeutic potential, targeting PPIs present unique hurdles for drug discovery: |
| • |
Large, flat interfaces (1,500-3,000 Ų), complicating effective drug
binding. |
| • |
Lack of deep binding pockets, resulting in low drug affinity. |
| • |
Poor drug-likeness, often violating Lipinski’s “Rule of Five.” |
| • |
Complex validation, requiring extensive biological assays. |
| • |
High intrinsic protein affinity, making disruption difficult. |
| • |
Complex validation, requiring extensive biological assays. |
|
| Three Types of PPI Inhibitors |
PPI inhibitors are categorized into three groups, each with distinct
advantages and limitations[3][4]: |
| Types |
Advantages |
Disadvantages |
| Small-molecule drugs |
Ideal pharmacokinetic characteristics and simple administration. |
Lower selectivity, poor solubility, and challenging drug development. |
| Antibodies |
High target specificity. |
Limited to binding cell surface or extracellular proteins; may cause off-target effects and adverse reactions. |
| Peptides |
High affinity for PPIs and good target specificity. |
Poor stability under physiological conditions, susceptible to hydrolysis
by various enzymes, short half-life,
and low oral bioavailability. |
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| High-Throughput Screening (HTS) for PPI Inhibitors |
| HTS accelerates the discovery of PPI inhibitors by enabling rapid screening of vast compound libraries. However, conventional libraries often fail to address the unique structural demands of PPIs. |
| To bridge this gap, MedChemExpress (MCE) offers specialized libraries tailored for PPI research. The PPI inhibitor library includes some reported PPI inhibitors, which can improve the screening efficiency of PPI inhibitors. Cyclic peptides and macrocyclic compounds have good binding force and target selectivity for PPl targets due to their large spatial structure, making them suitable candidates for the development of PPl inhibitors. |
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Featured MCE Libraries for PPI Research |
|
| Product Name |
Description |
Cyclic Peptide Library
|
This library contains more than 90 cyclic peptides, and
the compounds have good binding affinity for protein
surfaces, and low toxicity. |
Protein-protein Interaction Inhibitor Library
|
This library includes over 600 reported PPI inhibitors,
mainly targeting some common PPI targets, such as
MDM2-p53, Keap1-Nrf2, PD-1/PD-L1, Myc-Max, etc. |
Macrocyclic Compound Library
|
This library contains over 400 compounds with
12-membered or larger rings, which can provide a larger
chemical space, thereby increasing the affinity and
selectivity for binding to the target. |
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| References: |
[1] Chem Soc Rev. 2015 Nov 21;44(22):8238-59.
[2] Curr Drug Metab. 2017;18(1):5-10.
[3] Acta Pharm Sin B. 2023 Oct;13(10):4060-4088.
[4] Signal Transduct Target Ther. 2023 Sep 6;8(1):335. |
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MCE
One-Stop Screening Platform
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MCE
Recombinant
Protein
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