Cargando…

Recent Advances in EPAC-Targeted Therapies: A Biophysical Perspective

The universal second messenger cAMP regulates diverse intracellular processes by interacting with ubiquitously expressed proteins, such as Protein Kinase A (PKA) and the Exchange Protein directly Activated by cAMP (EPAC). EPAC is implicated in multiple pathologies, thus several EPAC-specific inhibit...

Descripción completa

Detalles Bibliográficos
Autores principales: Ahmed, Alveena, Boulton, Stephen, Shao, Hongzhao, Akimoto, Madoka, Natarajan, Amarnath, Cheng, Xiaodong, Melacini, Giuseppe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912387/
https://www.ncbi.nlm.nih.gov/pubmed/31752286
http://dx.doi.org/10.3390/cells8111462
_version_ 1783479444041629696
author Ahmed, Alveena
Boulton, Stephen
Shao, Hongzhao
Akimoto, Madoka
Natarajan, Amarnath
Cheng, Xiaodong
Melacini, Giuseppe
author_facet Ahmed, Alveena
Boulton, Stephen
Shao, Hongzhao
Akimoto, Madoka
Natarajan, Amarnath
Cheng, Xiaodong
Melacini, Giuseppe
author_sort Ahmed, Alveena
collection PubMed
description The universal second messenger cAMP regulates diverse intracellular processes by interacting with ubiquitously expressed proteins, such as Protein Kinase A (PKA) and the Exchange Protein directly Activated by cAMP (EPAC). EPAC is implicated in multiple pathologies, thus several EPAC-specific inhibitors have been identified in recent years. However, the mechanisms and molecular interactions underlying the EPAC inhibition elicited by such compounds are still poorly understood. Additionally, being hydrophobic low molecular weight species, EPAC-specific inhibitors are prone to forming colloidal aggregates, which result in non-specific aggregation-based inhibition (ABI) in aqueous systems. Here, we review from a biophysical perspective the molecular basis of the specific and non-specific interactions of two EPAC antagonists—CE3F4R, a non-competitive inhibitor, and ESI-09, a competitive inhibitor of EPAC. Additionally, we discuss the value of common ABI attenuators (e.g., TX and HSA) to reduce false positives at the expense of introducing false negatives when screening aggregation-prone compounds. We hope this review provides the EPAC community effective criteria to evaluate similar compounds, aiding in the optimization of existing drug leads, and informing the development of the next generation of EPAC-specific inhibitors.
format Online
Article
Text
id pubmed-6912387
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-69123872020-01-02 Recent Advances in EPAC-Targeted Therapies: A Biophysical Perspective Ahmed, Alveena Boulton, Stephen Shao, Hongzhao Akimoto, Madoka Natarajan, Amarnath Cheng, Xiaodong Melacini, Giuseppe Cells Review The universal second messenger cAMP regulates diverse intracellular processes by interacting with ubiquitously expressed proteins, such as Protein Kinase A (PKA) and the Exchange Protein directly Activated by cAMP (EPAC). EPAC is implicated in multiple pathologies, thus several EPAC-specific inhibitors have been identified in recent years. However, the mechanisms and molecular interactions underlying the EPAC inhibition elicited by such compounds are still poorly understood. Additionally, being hydrophobic low molecular weight species, EPAC-specific inhibitors are prone to forming colloidal aggregates, which result in non-specific aggregation-based inhibition (ABI) in aqueous systems. Here, we review from a biophysical perspective the molecular basis of the specific and non-specific interactions of two EPAC antagonists—CE3F4R, a non-competitive inhibitor, and ESI-09, a competitive inhibitor of EPAC. Additionally, we discuss the value of common ABI attenuators (e.g., TX and HSA) to reduce false positives at the expense of introducing false negatives when screening aggregation-prone compounds. We hope this review provides the EPAC community effective criteria to evaluate similar compounds, aiding in the optimization of existing drug leads, and informing the development of the next generation of EPAC-specific inhibitors. MDPI 2019-11-19 /pmc/articles/PMC6912387/ /pubmed/31752286 http://dx.doi.org/10.3390/cells8111462 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Ahmed, Alveena
Boulton, Stephen
Shao, Hongzhao
Akimoto, Madoka
Natarajan, Amarnath
Cheng, Xiaodong
Melacini, Giuseppe
Recent Advances in EPAC-Targeted Therapies: A Biophysical Perspective
title Recent Advances in EPAC-Targeted Therapies: A Biophysical Perspective
title_full Recent Advances in EPAC-Targeted Therapies: A Biophysical Perspective
title_fullStr Recent Advances in EPAC-Targeted Therapies: A Biophysical Perspective
title_full_unstemmed Recent Advances in EPAC-Targeted Therapies: A Biophysical Perspective
title_short Recent Advances in EPAC-Targeted Therapies: A Biophysical Perspective
title_sort recent advances in epac-targeted therapies: a biophysical perspective
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912387/
https://www.ncbi.nlm.nih.gov/pubmed/31752286
http://dx.doi.org/10.3390/cells8111462
work_keys_str_mv AT ahmedalveena recentadvancesinepactargetedtherapiesabiophysicalperspective
AT boultonstephen recentadvancesinepactargetedtherapiesabiophysicalperspective
AT shaohongzhao recentadvancesinepactargetedtherapiesabiophysicalperspective
AT akimotomadoka recentadvancesinepactargetedtherapiesabiophysicalperspective
AT natarajanamarnath recentadvancesinepactargetedtherapiesabiophysicalperspective
AT chengxiaodong recentadvancesinepactargetedtherapiesabiophysicalperspective
AT melacinigiuseppe recentadvancesinepactargetedtherapiesabiophysicalperspective