Modulating protein–protein interaction networks in protein homeostasis

Mengqi Zhong, Gregory M. Lee, Eline Sijbesma, Christian Ottmann, Michelle R. Arkin (Corresponding author)

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Abstract

Protein–protein interactions (PPIs) occur in complex networks. These networks are highly dependent on cellular context and can be extensively altered in disease states such as cancer and viral infection. In recent years, there has been significant progress in developing inhibitors that target individual PPIs either orthosterically (at the interface) or allosterically. These molecules can now be used as tools to dissect PPI networks. Here, we review recent examples that highlight the use of small molecules and engineered proteins to probe PPIs within the complex networks that regulate protein homeostasis. Researchers have discovered multiple mechanisms to modulate PPIs involved in host/viral interactions, deubiquitinases, the ATPase p97/VCP, and HSP70 chaperones. However, few studies have evaluated the effect of such modulators on the target's network or have compared the biological implications of different modulation strategies. Such studies will have an important impact on next generation therapeutics.

Original languageEnglish
Pages (from-to)55-65
Number of pages11
JournalCurrent Opinion in Chemical Biology
Volume50
DOIs
Publication statusPublished - 1 Jun 2019

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Protein Interaction Maps
Complex networks
Homeostasis
Molecules
Virus Diseases
Modulators
Proteins
Research Personnel
Modulation
Neoplasms
Therapeutics
Deubiquitinating Enzymes
p97 ATPase

Cite this

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abstract = "Protein–protein interactions (PPIs) occur in complex networks. These networks are highly dependent on cellular context and can be extensively altered in disease states such as cancer and viral infection. In recent years, there has been significant progress in developing inhibitors that target individual PPIs either orthosterically (at the interface) or allosterically. These molecules can now be used as tools to dissect PPI networks. Here, we review recent examples that highlight the use of small molecules and engineered proteins to probe PPIs within the complex networks that regulate protein homeostasis. Researchers have discovered multiple mechanisms to modulate PPIs involved in host/viral interactions, deubiquitinases, the ATPase p97/VCP, and HSP70 chaperones. However, few studies have evaluated the effect of such modulators on the target's network or have compared the biological implications of different modulation strategies. Such studies will have an important impact on next generation therapeutics.",
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Modulating protein–protein interaction networks in protein homeostasis. / Zhong, Mengqi; Lee, Gregory M.; Sijbesma, Eline; Ottmann, Christian; Arkin, Michelle R. (Corresponding author).

In: Current Opinion in Chemical Biology, Vol. 50, 01.06.2019, p. 55-65.

Research output: Contribution to journalReview articleAcademicpeer-review

TY - JOUR

T1 - Modulating protein–protein interaction networks in protein homeostasis

AU - Zhong, Mengqi

AU - Lee, Gregory M.

AU - Sijbesma, Eline

AU - Ottmann, Christian

AU - Arkin, Michelle R.

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AB - Protein–protein interactions (PPIs) occur in complex networks. These networks are highly dependent on cellular context and can be extensively altered in disease states such as cancer and viral infection. In recent years, there has been significant progress in developing inhibitors that target individual PPIs either orthosterically (at the interface) or allosterically. These molecules can now be used as tools to dissect PPI networks. Here, we review recent examples that highlight the use of small molecules and engineered proteins to probe PPIs within the complex networks that regulate protein homeostasis. Researchers have discovered multiple mechanisms to modulate PPIs involved in host/viral interactions, deubiquitinases, the ATPase p97/VCP, and HSP70 chaperones. However, few studies have evaluated the effect of such modulators on the target's network or have compared the biological implications of different modulation strategies. Such studies will have an important impact on next generation therapeutics.

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