NMR-based design and evaluation of novel bidentate inhibitors of the protein tyrosine phosphatase YopH.
We describe the use of a furanyl salicyl nitroxide derivative ('spin-labeled' compound), as a paramagnetic phosphotyrosine mimetic, to carry out a second-site screening by NMR against the PTPase YopH from Yersinia pestis. Using such a fragment-based screening approach we identified several small molecules targeting YopH that bind at sites adjacent to the spin-labeled compound. These second-site fragments were subsequently used to design and synthesize bidentate YopH inhibitors with submicromolar in vitro inhibition, selectivity against the human PTPase PTP1B, and cellular activity against Y. pseudotuberculosis. These initial compounds could result useful in elucidating the structural determinants necessary for YopH inhibition and may help in the design of even more active, selective and cell permeable compounds for the development of novel therapies against Yersiniae.
Leone
Marilisa
M
Infectious and Inflammatory Disease Center and Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037 , USA.
Barile
Elisa
E
Vazquez
Jesus
J
Mei
Angel
A
Guiney
Donald
D
Dahl
Russel
R
Pellecchia
Maurizio
M
D001425:Bacterial Outer Membrane Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D015007:Yersinia / Q000187:drug effects; D015009:Yersinia Infections / Q000188:drug therapy*
D001425:Bacterial Outer Membrane Proteins; D054852:Small Molecule Libraries; D017027:Protein Tyrosine Phosphatases; C067571:yopH protein, Yersinia
Methods. 2007 Jul;42(3):250-60
17532512
Mol Microbiol. 1998 Sep;29(5):1263-74
9767593
Philos Trans R Soc Lond B Biol Sci. 2000 May 29;355(1397):681-93
10874740
Chembiochem. 2002 Mar 1;3(2-3):167-73
11921394
J Bacteriol. 2000 Jun;182(11):3183-90
10809698
Mol Interv. 2006 Oct;6(5):266-72
17035667
J Comput Aided Mol Des. 1997 Sep;11(5):425-45
9385547
Nat Rev Drug Discov. 2002 Mar;1(3):211-9
12120505
Science. 1990 Aug 3;249(4968):553-6
2166336
J Am Chem Soc. 2001 Apr 4;123(13):3149-50
11457032
Infect Immun. 2002 Dec;70(12):7126-35
12438395
Bioorg Med Chem Lett. 2005 May 16;15(10):2503-7
15863305
Nat Rev Drug Discov. 2008 Sep;7(9):738-45
19172689
J Mol Graph. 1994 Jun;12(2):98-105
7918258
Expert Opin Ther Targets. 2006 Feb;10(1):157-77
16441235
J Med Chem. 1997 Sep 26;40(20):3144-50
9379433
Biochemistry. 2003 Nov 18;42(45):13113-21
14609321
Clin Vaccine Immunol. 2007 Sep;14(9):1235-8
17652523
Mol Microbiol. 1995 Oct;18(1):135-50
8596454
Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):8778-83
10922034
Chem Biol Drug Des. 2009 Apr;73(4):369-79
19291099
J Med Chem. 2008 Jun 26;51(12):3460-5
18494454
Expert Opin Ther Targets. 2004 Dec;8(6):597-611
15584865
J Biol Chem. 2004 Feb 6;279(6):4922-8
14623872
J Biomol NMR. 1995 Jul;6(1):1-10
22911575
J Biol Chem. 2005 Mar 11;280(10):9400-8
15615724
J Med Chem. 2009 Nov 12;52(21):6716-23
19888758
J Biomol NMR. 2001 Sep;21(1):69-70
11693571
Curr Top Med Chem. 2003;3(1):69-80
12570778
Biochemistry. 2002 Sep 24;41(38):11425-37
12234185
Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12602-6
16891420
Chem Biol. 2005 Sep;12(9):961-71
16183020
J Med Chem. 2007 May 3;50(9):2137-43
17394300
Cell Microbiol. 2000 Oct;2(5):401-14
11207596
Chemistry. 2006 Mar 20;12(10):2658-62
16121405