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Deposition of amyloid fibrils, consisting primarily of Aβ(40) and Aβ(42) peptides, in the extracellular space in the brain is a major characteristic of Alzheimer's disease (AD). We recently developed new (to our knowledge) drug candidates for AD that inhibit the fibril formation of Aβ peptides and eliminate their neurotoxicity. We performed all-atom molecular-dynamics simulations on the Aβ(42) monomer at its α-helical conformation and a pentamer fibril fragment of Aβ(42) peptide with or without LRL and fluorene series compounds to investigate the mechanism of inhibition. The results show that the active drug candidates, LRL22 (EC(50) = 0.734 μM) and K162 (EC(50) = 0.080 μM), stabilize hydrophobic core I of Aβ(42) peptide (residues 17-21) to its α-helical conformation by interacting specifically in this region. The nonactive drug candidates, LRL27 (EC(50) > 10 μM) and K182 (EC(50) > 5 μM), have little to no similar effect. This explains the different behavior of the drug candidates in experiments. Of more importance, this phenomenon indicates that hydrophobic core I of the Aβ(42) peptide plays a major mechanistic role in the formation of amyloid fibrils, and paves the way for the development of new drugs against AD.

Titel:	Alzheimer's disease drug candidates stabilize A-β protein native structure by interacting with the hydrophobic core.
Autor/in / Beteiligte Person:	Li, J ; Liu, R ; Lam, KS ; Jin, LW ; Duan, Y
Link:	Full Text Finder (Volltext)
Zeitschrift:	Biophysical journal, Jg. 100 (2011-02-16), Heft 4, S. 1076-82
Veröffentlichung:	Cambridge, MA : Cell Press ; <i>Original Publication</i>: New York, Published by Rockefeller University Press [etc.] for the Biophysical Society., 2011
Medientyp:	academicJournal
ISSN:	1542-0086 (electronic)
DOI:	10.1016/j.bpj.2010.12.3741
Schlagwort:	Fluorenes chemistry Fluorenes therapeutic use Hydrogen Bonding Models, Molecular Protein Stability Protein Structure, Quaternary Protein Structure, Secondary Thermodynamics Alzheimer Disease drug therapy Amyloid beta-Peptides chemistry Amyloid beta-Peptides metabolism Fluorenes metabolism Hydrophobic and Hydrophilic Interactions
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Language: English [Biophys J] 2011 Feb 16; Vol. 100 (4), pp. 1076-82. MeSH Terms: Hydrophobic and Hydrophilic Interactions* ; Alzheimer Disease / drug therapy ; Amyloid beta-Peptides / chemistry ; Amyloid beta-Peptides / metabolism ; Fluorenes / metabolism ; Fluorenes / chemistry ; Fluorenes / therapeutic use ; Hydrogen Bonding ; Models, Molecular ; Protein Stability ; Protein Structure, Quaternary ; Protein Structure, Secondary ; Thermodynamics References: Proc Natl Acad Sci U S A. 1998 May 26;95(11):6448-53. (PMID: 9600986) ; J Biol Chem. 1996 Dec 13;271(50):31894-902. (PMID: 8943233) ; Ann N Y Acad Sci. 1993 Sep 24;695:144-8. (PMID: 8239273) ; Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1550-5. (PMID: 9037091) ; J Med Chem. 2006 Oct 5;49(20):6057-64. (PMID: 17004719) ; J Mol Biol. 2001 Oct 5;312(5):1103-19. (PMID: 11580253) ; Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9191-6. (PMID: 19458258) ; Trends Biochem Sci. 1999 Sep;24(9):329-32. (PMID: 10470028) ; Chembiochem. 2006 Feb;7(2):257-67. (PMID: 16444756) ; Chem Biol Drug Des. 2006 Jan;67(1):27-37. (PMID: 16492146) ; Biochemistry. 1993 May 11;32(18):4693-7. (PMID: 8490014) ; Curr Opin Struct Biol. 2000 Feb;10(1):60-8. (PMID: 10679462) ; J Mol Biol. 2006 Apr 21;358(1):106-19. (PMID: 16499926) ; Neurobiol Aging. 2004 Nov-Dec;25(10):1263-72. (PMID: 15465622) ; J Biol Chem. 1998 Aug 14;273(33):21153-60. (PMID: 9694871) ; FEBS Lett. 2007 Mar 20;581(6):1161-5. (PMID: 17328898) ; J Comput Chem. 2003 Dec;24(16):1999-2012. (PMID: 14531054) ; J Comput Chem. 2005 Dec;26(16):1668-88. (PMID: 16200636) ; J Comput Chem. 2004 Jul 15;25(9):1157-74. (PMID: 15116359) ; Int J Biol Macromol. 2007 Aug 1;41(3):295-300. (PMID: 17477968) ; J Biomed Biotechnol. 2006;2006(3):58406. (PMID: 17047308) ; J Mol Biol. 1992 Jun 20;225(4):1075-93. (PMID: 1613791) ; Biochemistry. 1998 Aug 4;37(31):11064-77. (PMID: 9693002) ; Science. 2006 Nov 3;314(5800):781-4. (PMID: 17082448) ; J Biol Chem. 2003 Feb 28;278(9):7010-8. (PMID: 12493731) ; Nature. 2006 Mar 16;440(7082):352-7. (PMID: 16541076) ; Nat Med. 1996 Jan;2(1):93-5. (PMID: 8564851) ; J Am Chem Soc. 2006 Dec 20;128(50):16159-68. (PMID: 17165769) ; Neurobiol Aging. 2010 Oct;31(10):1690-9. (PMID: 19022536) ; Proc Natl Acad Sci U S A. 2005 Nov 29;102(48):17342-7. (PMID: 16293696) ; Philos Trans R Soc Lond B Biol Sci. 2001 Feb 28;356(1406):133-45. (PMID: 11260793) ; Chem Biol Drug Des. 2007 May;69(5):356-61. (PMID: 17539828) ; Neuroscience. 2005;132(1):123-35. (PMID: 15780472) ; Neurobiol Dis. 1998 Oct;5(4):281-6. (PMID: 9848098) ; Acc Chem Res. 2000 Dec;33(12):889-97. (PMID: 11123888) ; Biochem Biophys Res Commun. 2005 Mar 25;328(4):816-23. (PMID: 15707952) ; J Neurosci. 2005 Mar 9;25(10):2455-62. (PMID: 15758153) ; J Mol Biol. 2007 Feb 9;366(1):275-85. (PMID: 17166516) Grant Information: R01 GM067168 United States GM NIGMS NIH HHS; R01 GM079383 United States GM NIGMS NIH HHS; GM67168 United States GM NIGMS NIH HHS; GM79383 United States GM NIGMS NIH HHS Substance Nomenclature: 0 (Amyloid beta-Peptides) ; 0 (Fluorenes) Entry Date(s): Date Created: 20110216 Date Completed: 20110411 Latest Revision: 20211020 Update Code: 20231215 PubMed Central ID: PMC3037571

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Alzheimer's disease drug candidates stabilize A-β protein native structure by interacting with the hydrophobic core.