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Title: Using Fragment Cocktail Crystallography to Assist Inhibitor Design of Trypanosoma Brucei Nucleoside 2-Deoxyribosyltransferase

Abstract

No abstract prepared.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; more »; ; « less
Publication Date:
Research Org.:
Stanford Linear Accelerator Center (SLAC)
Sponsoring Org.:
USDOE
OSTI Identifier:
897451
Report Number(s):
SLAC-REPRINT-2006-167
TRN: US200705%%327
DOE Contract Number:
AC02-76SF00515
Resource Type:
Journal Article
Resource Relation:
Journal Name: J.Med.Chem.49:5939-5945,2006
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; CRYSTALLOGRAPHY; DESIGN; NUCLEOSIDES; TRYPANOSOMA; Other,OTHER

Citation Formats

A - Bosch, J., - Robien, M.A., - Mehlin, C., - Boni, E., - Riechers, A., - Buckner, F.S., - Van Voorhis, W.C., - Myler, P.J., - Worthey, E.A., - DeTitta, G., - Luft, J.R., - Lauricella, A., - Gulde, S., - Anderson, L.A., - Kalyuzhniy, O., - Neely, H.M., - Ross, J., - Earnest, T.N., - Soltis, M., - Schoenfeld, L., - Zucker, F., and /Washington U., Seattle /LBL, Berkeley /SLAC, SSRL. Using Fragment Cocktail Crystallography to Assist Inhibitor Design of Trypanosoma Brucei Nucleoside 2-Deoxyribosyltransferase. United States: N. p., 2007. Web.
A - Bosch, J., - Robien, M.A., - Mehlin, C., - Boni, E., - Riechers, A., - Buckner, F.S., - Van Voorhis, W.C., - Myler, P.J., - Worthey, E.A., - DeTitta, G., - Luft, J.R., - Lauricella, A., - Gulde, S., - Anderson, L.A., - Kalyuzhniy, O., - Neely, H.M., - Ross, J., - Earnest, T.N., - Soltis, M., - Schoenfeld, L., - Zucker, F., & /Washington U., Seattle /LBL, Berkeley /SLAC, SSRL. Using Fragment Cocktail Crystallography to Assist Inhibitor Design of Trypanosoma Brucei Nucleoside 2-Deoxyribosyltransferase. United States.
A - Bosch, J., - Robien, M.A., - Mehlin, C., - Boni, E., - Riechers, A., - Buckner, F.S., - Van Voorhis, W.C., - Myler, P.J., - Worthey, E.A., - DeTitta, G., - Luft, J.R., - Lauricella, A., - Gulde, S., - Anderson, L.A., - Kalyuzhniy, O., - Neely, H.M., - Ross, J., - Earnest, T.N., - Soltis, M., - Schoenfeld, L., - Zucker, F., and /Washington U., Seattle /LBL, Berkeley /SLAC, SSRL. Wed . "Using Fragment Cocktail Crystallography to Assist Inhibitor Design of Trypanosoma Brucei Nucleoside 2-Deoxyribosyltransferase". United States. doi:.
@article{osti_897451,
title = {Using Fragment Cocktail Crystallography to Assist Inhibitor Design of Trypanosoma Brucei Nucleoside 2-Deoxyribosyltransferase},
author = {A - Bosch, J. and - Robien, M.A. and - Mehlin, C. and - Boni, E. and - Riechers, A. and - Buckner, F.S. and - Van Voorhis, W.C. and - Myler, P.J. and - Worthey, E.A. and - DeTitta, G. and - Luft, J.R. and - Lauricella, A. and - Gulde, S. and - Anderson, L.A. and - Kalyuzhniy, O. and - Neely, H.M. and - Ross, J. and - Earnest, T.N. and - Soltis, M. and - Schoenfeld, L. and - Zucker, F. and /Washington U., Seattle /LBL, Berkeley /SLAC, SSRL},
abstractNote = {No abstract prepared.},
doi = {},
journal = {J.Med.Chem.49:5939-5945,2006},
number = ,
volume = ,
place = {United States},
year = {Wed Jan 10 00:00:00 EST 2007},
month = {Wed Jan 10 00:00:00 EST 2007}
}
  • Glycogen synthase kinase-3 (GSK-3) is a drug target under intense investigation in pharmaceutical companies and constitutes an attractive piggyback target for eukaryotic pathogens. Two different GSKs are found in trypanosomatids, one about 150 residues shorter than the other. GSK-3 short (GeneDB: Tb927.10.13780) has previously been validated genetically as a drug target in Trypanosoma brucei by RNAi induced growth retardation; and chemically by correlation between enzyme and in vitro growth inhibition. Here, we report investigation of the equivalent GSK-3 short enzymes of L. major (LmjF18.0270) and L. infantum (LinJ18_V3.0270, identical in amino acid sequences to LdonGSK-3 short) and a crystal structuremore » of LmajGSK-3 short at 2 Å resolution. The inhibitor structure-activity relationships (SARs) of L. major and L. infantum are virtually identical, suggesting that inhibitors could be useful for both cutaneous and visceral leishmaniasis. Leishmania spp. GSK-3 short has different inhibitor SARs than TbruGSK-3 short, which can be explained mostly by two variant residues in the ATP-binding pocket. Indeed, mutating these residues in the ATP-binding site of LmajGSK-3 short to the TbruGSK-3 short equivalents results in a mutant LmajGSK-3 short enzyme with SAR more similar to that of TbruGSK-3 short. The differences between human GSK-3β (HsGSK-3β) and LmajGSK-3 short SAR suggest that compounds which selectively inhibit LmajGSK-3 short may be found.« less
  • Trypanosomes use trans splicing to place a common 39-nucleotide spliced-leader sequence on the 5' ends of all of their mRNAs. To identify likely participants in this reaction, the authors used antiserum directed against the characteristic U RNA 2,2,7-trimehtylguanosine (TMG) cap to immunoprecipitate six candidate U RNAs from total trypanosome RNA. Genomic Southern analysis using oligonucleotide probes constructed frm partial RNA sequence indicated that the four largest RNAs (A through D) are encoded by single-copy genes that are not closely linked to one another. The authors have cloned and sequenced these genes, mapped the 5' ends of the encoded RNAs,and identifiedmore » three of the RNAs as the trypanosome U2, U4, and U6 analogs by virtue of their sequences and structural homologies with the corresponding metazoan U RNAs. The fourth RNA, RNA B (144 nucleotides), was not sufficiently similar to known U RNAs to allow them to propose an identity. Surprisingly, none of the U RNAs contained the consensus Sm antigen-binding site, a feature totally conserved among several classes of U RNAs, including U2 and U4. Similarly, the sequence of the U2 RNA region shown to be involved in pre-mRNA branchpoint recognition in yeast, and exactly conserved in metazoan U2 RNAs, was totally divergent in trypanosomes. Like all other U6 RNAs, trypanosome U6 did not contain a TMG cap and was immunoprecipitated from deproteinized RNA by anti-TMG antibody because of its association with the TMG-capped U4 RNA. These two RNAs contained extensive regions of sequence complementarity which phylogenetically support the secondary-structure model proposed by D.A. Brow and C. Guthrie (Nature (London) 334:213-218, 1988) for the organization of the analogous yeast U4-U6 complex.« less
  • Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40). This compound displays a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration.