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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-11-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/8/11/1462 |
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| author | Alveena Ahmed Stephen Boulton Hongzhao Shao Madoka Akimoto Amarnath Natarajan Xiaodong Cheng Giuseppe Melacini |
| author_facet | Alveena Ahmed Stephen Boulton Hongzhao Shao Madoka Akimoto Amarnath Natarajan Xiaodong Cheng Giuseppe Melacini |
| author_sort | Alveena Ahmed |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-12T11:05:29Z |
| format | Article |
| id | doaj.art-686cdc03242a40d09e222d41dbdac437 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T11:05:29Z |
| publishDate | 2019-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-686cdc03242a40d09e222d41dbdac4372023-09-02T04:04:02ZengMDPI AGCells2073-44092019-11-01811146210.3390/cells8111462cells8111462Recent Advances in EPAC-Targeted Therapies: A Biophysical PerspectiveAlveena Ahmed0Stephen Boulton1Hongzhao Shao2Madoka Akimoto3Amarnath Natarajan4Xiaodong Cheng5Giuseppe Melacini6Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, CanadaDepartment of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, CanadaDepartment of Chemistry and Chemical Biology, McMaster University, Hamilton, ON L8S 4L8, CanadaDepartment of Chemistry and Chemical Biology, McMaster University, Hamilton, ON L8S 4L8, CanadaEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Integrative Biology & Pharmacology, University of Texas Health Science Center at Houston, Houston, TX 77030, USADepartment of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, CanadaThe 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.https://www.mdpi.com/2073-4409/8/11/1462epacaggregation-based inhibitionallosterycampdynamicsdrug designnmrprotein-ligand bindingscreeningsignaling |
| spellingShingle | Alveena Ahmed Stephen Boulton Hongzhao Shao Madoka Akimoto Amarnath Natarajan Xiaodong Cheng Giuseppe Melacini Recent Advances in EPAC-Targeted Therapies: A Biophysical Perspective Cells epac aggregation-based inhibition allostery camp dynamics drug design nmr protein-ligand binding screening signaling |
| 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 | epac aggregation-based inhibition allostery camp dynamics drug design nmr protein-ligand binding screening signaling |
| url | https://www.mdpi.com/2073-4409/8/11/1462 |
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