Phosphodiesterase 5 (PDE5): Structure-function regulation and therapeutic applications of inhibitors
<p dir="ltr">Phosphodiesterase 5 (PDE5) is one of the most well-studied phosphodiesterases (PDEs) that specifically targets cGMP typically generated by nitric oxide (NO)-mediated activation of the soluble guanylyl cyclase. Given the crucial role of cGMP generated through the activati...
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2021
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| _version_ | 1864513559488102400 |
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| author | Wesam S. Ahmed (10170053) |
| author2 | Anupriya M. Geethakumari (17052375) Kabir H. Biswas (5705864) |
| author2_role | author author |
| author_facet | Wesam S. Ahmed (10170053) Anupriya M. Geethakumari (17052375) Kabir H. Biswas (5705864) |
| author_role | author |
| dc.creator.none.fl_str_mv | Wesam S. Ahmed (10170053) Anupriya M. Geethakumari (17052375) Kabir H. Biswas (5705864) |
| dc.date.none.fl_str_mv | 2021-02-21T00:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1016/j.biopha.2020.111128 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Phosphodiesterase_5_PDE5_Structure-function_regulation_and_therapeutic_applications_of_inhibitors/24204144 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Cardiovascular medicine and haematology Pharmacology and pharmaceutical sciences Cyclic guanosine monophosphate (cGMP) Cardiovascular diseases Clinical indications Pharmacological inhibitors Phosphodiesterase 5 (PDE5) Therapeutic applications |
| dc.title.none.fl_str_mv | Phosphodiesterase 5 (PDE5): Structure-function regulation and therapeutic applications of inhibitors |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">Phosphodiesterase 5 (PDE5) is one of the most well-studied phosphodiesterases (PDEs) that specifically targets cGMP typically generated by nitric oxide (NO)-mediated activation of the soluble guanylyl cyclase. Given the crucial role of cGMP generated through the activation of this cellular signaling pathway in a variety of physiologically processes, pharmacological inhibition of PDE5 has been demonstrated to have several therapeutic applications including erectile dysfunction and pulmonary arterial hypertension. While they are designed to inhibit PDE5, the inhibitors show different affinities and specificities against all PDE subtypes. Additionally, they have been shown to induce allosteric structural changes in the protein. These are mostly attributed to their chemical structure and, therefore, binding interactions with PDE catalytic domains. Therefore, understanding how these inhibitors interact with PDE5 and the structural basis of their selectivity is critically important for the design of novel, highly selective PDE5 inhibitors. Here, we review the structure of PDE5, how its function is regulated, and discuss the clinically available inhibitors that target phosphodiesterase 5, aiming to better understand the structural bases of their affinity and specificity. We also discuss the therapeutic indications of these inhibitors and the potential of repurposing for a wider range of clinical applications.</p><h2>Other Information</h2><p dir="ltr">Published in: Biomedicine & Pharmacotherapy<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1016/j.biopha.2020.111128" target="_blank">https://dx.doi.org/10.1016/j.biopha.2020.111128</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_7aeda6a052d1b9abc7b98d03eebc796d |
| identifier_str_mv | 10.1016/j.biopha.2020.111128 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/24204144 |
| publishDate | 2021 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Phosphodiesterase 5 (PDE5): Structure-function regulation and therapeutic applications of inhibitorsWesam S. Ahmed (10170053)Anupriya M. Geethakumari (17052375)Kabir H. Biswas (5705864)Biomedical and clinical sciencesCardiovascular medicine and haematologyPharmacology and pharmaceutical sciencesCyclic guanosine monophosphate (cGMP)Cardiovascular diseasesClinical indicationsPharmacological inhibitorsPhosphodiesterase 5 (PDE5)Therapeutic applications<p dir="ltr">Phosphodiesterase 5 (PDE5) is one of the most well-studied phosphodiesterases (PDEs) that specifically targets cGMP typically generated by nitric oxide (NO)-mediated activation of the soluble guanylyl cyclase. Given the crucial role of cGMP generated through the activation of this cellular signaling pathway in a variety of physiologically processes, pharmacological inhibition of PDE5 has been demonstrated to have several therapeutic applications including erectile dysfunction and pulmonary arterial hypertension. While they are designed to inhibit PDE5, the inhibitors show different affinities and specificities against all PDE subtypes. Additionally, they have been shown to induce allosteric structural changes in the protein. These are mostly attributed to their chemical structure and, therefore, binding interactions with PDE catalytic domains. Therefore, understanding how these inhibitors interact with PDE5 and the structural basis of their selectivity is critically important for the design of novel, highly selective PDE5 inhibitors. Here, we review the structure of PDE5, how its function is regulated, and discuss the clinically available inhibitors that target phosphodiesterase 5, aiming to better understand the structural bases of their affinity and specificity. We also discuss the therapeutic indications of these inhibitors and the potential of repurposing for a wider range of clinical applications.</p><h2>Other Information</h2><p dir="ltr">Published in: Biomedicine & Pharmacotherapy<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1016/j.biopha.2020.111128" target="_blank">https://dx.doi.org/10.1016/j.biopha.2020.111128</a></p>2021-02-21T00:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1016/j.biopha.2020.111128https://figshare.com/articles/journal_contribution/Phosphodiesterase_5_PDE5_Structure-function_regulation_and_therapeutic_applications_of_inhibitors/24204144CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/242041442021-02-21T00:00:00Z |
| spellingShingle | Phosphodiesterase 5 (PDE5): Structure-function regulation and therapeutic applications of inhibitors Wesam S. Ahmed (10170053) Biomedical and clinical sciences Cardiovascular medicine and haematology Pharmacology and pharmaceutical sciences Cyclic guanosine monophosphate (cGMP) Cardiovascular diseases Clinical indications Pharmacological inhibitors Phosphodiesterase 5 (PDE5) Therapeutic applications |
| status_str | publishedVersion |
| title | Phosphodiesterase 5 (PDE5): Structure-function regulation and therapeutic applications of inhibitors |
| title_full | Phosphodiesterase 5 (PDE5): Structure-function regulation and therapeutic applications of inhibitors |
| title_fullStr | Phosphodiesterase 5 (PDE5): Structure-function regulation and therapeutic applications of inhibitors |
| title_full_unstemmed | Phosphodiesterase 5 (PDE5): Structure-function regulation and therapeutic applications of inhibitors |
| title_short | Phosphodiesterase 5 (PDE5): Structure-function regulation and therapeutic applications of inhibitors |
| title_sort | Phosphodiesterase 5 (PDE5): Structure-function regulation and therapeutic applications of inhibitors |
| topic | Biomedical and clinical sciences Cardiovascular medicine and haematology Pharmacology and pharmaceutical sciences Cyclic guanosine monophosphate (cGMP) Cardiovascular diseases Clinical indications Pharmacological inhibitors Phosphodiesterase 5 (PDE5) Therapeutic applications |