Exploration of icariin analog structure space reveals key features driving potent inhibition of human phosphodiesterase-5
Autoři:
Yasmin Chau aff001; Fu-Shuang Li aff001; Olesya Levsh aff001; Jing-Ke Weng aff001
Působiště autorů:
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America
aff001; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
aff002
Vyšlo v časopise:
PLoS ONE 14(9)
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pone.0222803
Souhrn
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.
Klíčová slova:
Biology and life sciences – Biochemistry – Physical sciences – Chemistry – Research and analysis methods – Enzymology – Enzymes – Proteins – Mathematics – Chemical compounds – Organic compounds – Organic chemistry – Statistics – Mathematical and statistical techniques – Statistical methods – Physics – Condensed matter physics – Solid state physics – Crystallography – Crystal structure – Chromatographic techniques – Liquid chromatography – High performance liquid chromatography – Bioassays and physiological analysis – Proteases – Serine proteases – Regression analysis – Physical chemistry – Chemical bonding – Hydrogen bonding – Enzyme inhibitors – Functional groups – Cell analysis – Cell viability testing
Zdroje
1. Friebe A, Sandner P, Schmidtko A. Meeting report of the 8th International Conference on cGMP “cGMP: generators, effectors, and therapeutic implications” at Bamberg, Germany, from June 23 to 25, 2017. Naunyn Schmiedebergs Arch Pharmacol. 2017;390: 1177–1188.
2. Surapisitchat J, Beavo JA. Phosphodiesterase Families. In: Bradshaw RA, Dennis EA, editors. Handbook of Cell Signaling. 2nd ed. Amsterdam; Boston: Elsevier/Academic Press; 2009. pp. 1409–1416.
3. Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Tissue-based map of the human proteome. Science. 2015;347: 1260419. doi: 10.1126/science.1260419 25613900
4. The Human Protein Atlas [Internet]. [cited 1 Jun 2019]. www.proteinatlas.org
5. Ahmad F, Murata T, Shimizu K, Degerman E, Maurice D, Manganiello V. Cyclic nucleotide phosphodiesterases: important signaling modulators and therapeutic targets. Oral Dis. 2015;21: e25–50. doi: 10.1111/odi.12275 25056711
6. Francis SH, Corbin JD. Phosphodiesterase-5. In: Bradshaw RA, Dennis EA, editors. Handbook of Cell Signaling. 2nd ed. Amsterdam; Boston: Elsevier/Academic Press; 2010. pp. 1439–1444.
7. Mehrotra N, Gupta M, Kovar A, Meibohm B. The role of pharmacokinetics and pharmacodynamics in phosphodiesterase-5 inhibitor therapy. Int J Impot Res. 2007;19: 253–264. doi: 10.1038/sj.ijir.3901522 16988721
8. Wright PJ. Comparison of phosphodiesterase type 5 (PDE5) inhibitors. Int J Clin Pract. 2006;60: 967–975. doi: 10.1111/j.1742-1241.2006.01049.x 16780568
9. Zhang X, Feng Q, Cote RH. Efficacy and selectivity of phosphodiesterase-targeted drugs in inhibiting photoreceptor phosphodiesterase (PDE6) in retinal photoreceptors. Invest Ophthalmol Vis Sci. 2005;46: 3060–3066. doi: 10.1167/iovs.05-0257 16123402
10. Sáenz de Tejada I. Vardenafil duration of action. Eur Urol. 2006;50: 901–902. doi: 10.1016/j.eururo.2006.07.041 16949729
11. Eardley I, Ellis P, Boolell M, Wulff M. Onset and duration of action of sildenafil for the treatment of erectile dysfunction. Br J Clin Pharmacol. 2002;53 Suppl 1: 61S–65S.
12. Mostafa T. Non-Sexual Implications of Phosphodiesterase Type 5 Inhibitors. Sexual Medicine Reviews. Elsevier; 2017;5: 170–199.
13. Li F-S, Weng J-K. Demystifying traditional herbal medicine with modern approach. Nature Plants. 2017;3: 17109. doi: 10.1038/nplants.2017.109 28758992
14. Ma H, He X, Yang Y, Li M, Hao D, Jia Z. The genus Epimedium: an ethnopharmacological and phytochemical review. J Ethnopharmacol. 2011;134: 519–541. doi: 10.1016/j.jep.2011.01.001 21215308
15. Wu H, Lien EJ, Lien LL. Chemical and pharmacological investigations of Epimedium species: a survey. Prog Drug Res. 2003;60: 1–57. 12790338
16. Xin ZC, Kim EK, Lin CS, Liu WJ, Tian L, Yuan YM, et al. Effects of icariin on cGMP-specific PDE5 and cAMP-specific PDE4 activities. Asian J Androl. 2003;5: 15–18. 12646997
17. Ning H, Xin Z-C, Lin G, Banie L, Lue TF, Lin C-S. Effects of icariin on phosphodiesterase-5 activity in vitro and cyclic guanosine monophosphate level in cavernous smooth muscle cells. Urology. 2006;68: 1350–1354. doi: 10.1016/j.urology.2006.09.031 17169663
18. Dell’Agli M, Galli GV, Dal Cero E, Belluti F, Matera R, Zironi E, et al. Potent inhibition of human phosphodiesterase-5 by icariin derivatives. J Nat Prod. 2008;71: 1513–1517. doi: 10.1021/np800049y 18778098
19. Xin Z, Euikyung K, Tian Z, Lin G, Guo Y. Icariin on relaxation effect of corpus cavernosum smooth muscle. Chin Sci Bull. 2001;46: 1186–1190.
20. Wang H, Liu Y, Huai Q, Cai J, Zoraghi R, Francis SH, et al. Multiple conformations of phosphodiesterase-5: Implications for enzyme function and drug development. J Biol Chem. 2006;281: 21469–21479. doi: 10.1074/jbc.M512527200 16735511
21. Huai Q, Liu Y, Francis SH, Corbin JD, Ke H. Crystal structures of phosphodiesterases 4 and 5 in complex with inhibitor 3-isobutyl-1-methylxanthine suggest a conformation determinant of inhibitor selectivity. J Biol Chem. 2004;279: 13095–13101. doi: 10.1074/jbc.M311556200 14668322
22. Wang H, Ye M, Robinson H, Francis SH, Ke H. Conformational Variations of Both Phosphodiesterase-5 and Inhibitors Provide the Structural Basis for the Physiological Effects of Vardenafil and Sildenafil. Mol Pharmacol. 2008;73: 104–110. doi: 10.1124/mol.107.040212 17959709
23. Shang N-N, Shao Y-X, Cai Y-H, Guan M, Huang M, Cui W, et al. Discovery of 3-(4-hydroxybenzyl)-1-(thiophen-2-yl) chromeno [2, 3-c] pyrrol-9 (2H)-one as a phosphodiesterase-5 inhibitor and its complex crystal structure. Biochem Pharmacol. Elsevier; 2014;89: 86–98.
24. Aldrich C, Bertozzi C, Georg GI, Kiessling L, Lindsley C, Liotta D, et al. The Ecstasy and Agony of Assay Interference Compounds. ACS Med Chem Lett. 2017;8: 379–382. doi: 10.1021/acsmedchemlett.7b00056 28435522
25. Zhang KYJ, Card GL, Suzuki Y, Artis DR, Fong D, Gillette S, et al. A glutamine switch mechanism for nucleotide selectivity by phosphodiesterases. Mol Cell. 2004;15: 279–286. doi: 10.1016/j.molcel.2004.07.005 15260978
26. Ke H, Wang H. Crystal structures of phosphodiesterases and implications on substrate specificity and inhibitor selectivity. Curr Top Med Chem. 2007;7: 391–403. doi: 10.2174/156802607779941242 17305581
27. Jiang X-R, Jimenez G, Chang E, Frolkis M, Kusler B, Sage M, et al. Telomerase expression in human somatic cells does not induce changes associated with a transformed phenotype. Nat Genet. 1999;21: 111–114. doi: 10.1038/5056 9916802
28. Pilz RB, Casteel DE. Regulation of Gene Expression by Cyclic GMP. Circulation Research. 2003;93: 1034–1046. doi: 10.1161/01.RES.0000103311.52853.48 14645134
29. Jingshan Shen, Shujun Zhang, Hongli Guo, Xinjian Chen, Yifeng Nian. Prenyl flavonoids, their preparation and use. World Patent. 2008014722A1.
30. Tipton KF, Armstrong RN, Bakker BM, Bairoch A, Cornish-Bowden A, Halling PJ, et al. Standards for Reporting Enzyme Data: The STRENDA Consortium: What it aims to do and why it should be helpful. Perspectives in Science. 2014;1: 131–137.
31. Kincaid RL, Manganiello VC. Assay of cyclic nucleotide phosphodiesterase using radiolabeled and fluorescent substrates. Methods Enzymol. 1988;159: 457–470. doi: 10.1016/0076-6879(88)59045-6 2842611
32. Dell’Agli M, Galli GV, Vrhovsek U, Mattivi F, Bosisio E. In vitro inhibition of human cGMP-specific phosphodiesterase-5 by polyphenols from red grapes. J Agric Food Chem. 2005; doi: 10.1021/jf048497 15769121
33. Bisswanger H. Practical Enzymology. 2nd ed. Wiley-Blackwell; 2012.
34. Hanwell MD, Curtis DE, Lonie DC, Vandermeersch T, Zurek E, Hutchison GR. Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. J Cheminform. 2012;4: 17. doi: 10.1186/1758-2946-4-17 22889332
35. Emsley P, Cowtan K. Coot: model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr. 2004;60: 2126–2132. doi: 10.1107/S0907444904019158 15572765
36. Emsley P, Lohkamp B, Scott WG, Cowtan K. Features and development of Coot. Acta Crystallogr D Biol Crystallogr. 2010;66: 486–501. doi: 10.1107/S0907444910007493 20383002
37. Lyskov S, Chou F-C, Conchúir SÓ, Der BS, Drew K, Kuroda D, et al. Serverification of molecular modeling applications: the Rosetta Online Server that Includes Everyone (ROSIE). PLoS One. 2013;8: e63906. doi: 10.1371/journal.pone.0063906 23717507
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