Exploration of icariin analog structure space reveals key features driving potent inhibition of human phosphodiesterase-5.

The natural product icariin inhibits human phosphodiesterase-5 (PDE5) and represents a unique pharmacophore for treating erectile dysfunction, pulmonary hypertension, and other diseases. In this study, we explore the available icariin-derived chemical scaffolds through medicinal chemistry to develop...

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Autores principales:	Yasmin Chau, Fu-Shuang Li, Olesya Levsh, Jing-Ke Weng
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/31d1213b0d3b4491a4776060b1a4f923
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spelling	oai:doaj.org-article:31d1213b0d3b4491a4776060b1a4f9232021-11-25T06:23:48ZExploration of icariin analog structure space reveals key features driving potent inhibition of human phosphodiesterase-5.1932-620310.1371/journal.pone.0222803https://doaj.org/article/31d1213b0d3b4491a4776060b1a4f9232019-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0222803https://doaj.org/toc/1932-6203The natural product icariin inhibits human phosphodiesterase-5 (PDE5) and represents a unique pharmacophore for treating erectile dysfunction, pulmonary hypertension, and other diseases. In this study, we explore the available icariin-derived chemical scaffolds through medicinal chemistry to develop novel icariin PDE5 inhibitors with improved potency and specificity. We synthesized six novel semi-synthetic icariin analogs as well as three naturally occurring icariin analogs, and characterized the structure-activity relationship in the context of human PDE5 inhibition using in vitro enzyme inhibition and kinetics assays and molecular modeling. Mammalian-cell-based assays and in vitro enzyme inhibition assays against human PDE6C further helped to identify the most potent and selective icariin analogs. Our results reveal the synergistic contribution of functional groups at the C3 and C7 positions of the icariin backbone towards PDE5 inhibition. Whereas a hydrophobic and flexible alkanol group at the C7 position is sufficient to enhance icariin analog potency, combining this group with a hydrophilic sugar group at the C3 position leads to further enhancement of potency and promotes specificity towards PDE5 versus PDE6C. In particular, compounds 3 and 7 exhibit Ki values of 0.036 ± 0.005 μM and 0.036 ± 0.007 μM towards PDE5 respectively, which are approaching those of commercial PDE5 inhibitors, and can effectively reduce GMP levels in cultured human BJ-hTERT cells. This study identifies novel icariin analogs as potent and selective PDE5 inhibitors poised to become lead compounds for further pharmaceutical development.Yasmin ChauFu-Shuang LiOlesya LevshJing-Ke WengPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 14, Iss 9, p e0222803 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yasmin Chau Fu-Shuang Li Olesya Levsh Jing-Ke Weng Exploration of icariin analog structure space reveals key features driving potent inhibition of human phosphodiesterase-5.
description	The natural product icariin inhibits human phosphodiesterase-5 (PDE5) and represents a unique pharmacophore for treating erectile dysfunction, pulmonary hypertension, and other diseases. In this study, we explore the available icariin-derived chemical scaffolds through medicinal chemistry to develop novel icariin PDE5 inhibitors with improved potency and specificity. We synthesized six novel semi-synthetic icariin analogs as well as three naturally occurring icariin analogs, and characterized the structure-activity relationship in the context of human PDE5 inhibition using in vitro enzyme inhibition and kinetics assays and molecular modeling. Mammalian-cell-based assays and in vitro enzyme inhibition assays against human PDE6C further helped to identify the most potent and selective icariin analogs. Our results reveal the synergistic contribution of functional groups at the C3 and C7 positions of the icariin backbone towards PDE5 inhibition. Whereas a hydrophobic and flexible alkanol group at the C7 position is sufficient to enhance icariin analog potency, combining this group with a hydrophilic sugar group at the C3 position leads to further enhancement of potency and promotes specificity towards PDE5 versus PDE6C. In particular, compounds 3 and 7 exhibit Ki values of 0.036 ± 0.005 μM and 0.036 ± 0.007 μM towards PDE5 respectively, which are approaching those of commercial PDE5 inhibitors, and can effectively reduce GMP levels in cultured human BJ-hTERT cells. This study identifies novel icariin analogs as potent and selective PDE5 inhibitors poised to become lead compounds for further pharmaceutical development.
format	article
author	Yasmin Chau Fu-Shuang Li Olesya Levsh Jing-Ke Weng
author_facet	Yasmin Chau Fu-Shuang Li Olesya Levsh Jing-Ke Weng
author_sort	Yasmin Chau
title	Exploration of icariin analog structure space reveals key features driving potent inhibition of human phosphodiesterase-5.
title_short	Exploration of icariin analog structure space reveals key features driving potent inhibition of human phosphodiesterase-5.
title_full	Exploration of icariin analog structure space reveals key features driving potent inhibition of human phosphodiesterase-5.
title_fullStr	Exploration of icariin analog structure space reveals key features driving potent inhibition of human phosphodiesterase-5.
title_full_unstemmed	Exploration of icariin analog structure space reveals key features driving potent inhibition of human phosphodiesterase-5.
title_sort	exploration of icariin analog structure space reveals key features driving potent inhibition of human phosphodiesterase-5.
publisher	Public Library of Science (PLoS)
publishDate	2019
url	https://doaj.org/article/31d1213b0d3b4491a4776060b1a4f923
work_keys_str_mv	AT yasminchau explorationoficariinanalogstructurespacerevealskeyfeaturesdrivingpotentinhibitionofhumanphosphodiesterase5 AT fushuangli explorationoficariinanalogstructurespacerevealskeyfeaturesdrivingpotentinhibitionofhumanphosphodiesterase5 AT olesyalevsh explorationoficariinanalogstructurespacerevealskeyfeaturesdrivingpotentinhibitionofhumanphosphodiesterase5 AT jingkeweng explorationoficariinanalogstructurespacerevealskeyfeaturesdrivingpotentinhibitionofhumanphosphodiesterase5
_version_	1718413733397528576

Exploration of icariin analog structure space reveals key features driving potent inhibition of human phosphodiesterase-5.

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