Allen D. Kline
Eli Lilly and Company
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Publication
Featured researches published by Allen D. Kline.
Journal of Virology | 2000
C. Cheng Kao; Xueyong Yang; Allen D. Kline; Q.May Wang; Donna Barket; Beverly A. Heinz
ABSTRACT The RNA-dependent RNA polymerase (RdRp) from hepatitis C virus (HCV), nonstructural protein 5B (NS5B), has recently been shown to direct de novo initiation using a number of complex RNA templates. In this study, we analyzed the features in simple RNA templates that are required to direct de novo initiation of RNA synthesis by HCV NS5B. NS5B was found to protect RNA fragments of 8 to 10 nucleotides (nt) from RNase digestion. However, NS5B could not direct RNA synthesis unless the template contained a stable secondary structure and a single-stranded sequence that contained at least one 3′ cytidylate. The structure of a 25-nt template, named SLD3, was determined by nuclear magnetic resonance spectroscopy to contain an 8-bp stem and a 6-nt single-stranded sequence. Systematic analysis of changes in SLD3 revealed which features in the stem, loop, and 3′ single-stranded sequence were required for efficient RNA synthesis. Also, chimeric molecules composed of DNA and RNA demonstrated that a DNA molecule containing a 3′-terminal ribocytidylate was able to direct RNA synthesis as efficiently as a sequence composed entirely of RNA. These results define the template sequence and structure sufficient to direct the de novo initiation of RNA synthesis by HCV RdRp.
Journal of Magnetic Resonance | 2003
Jiangli Yan; Allen D. Kline; Huaping Mo; Michael Shapiro; Edward R. Zartler
The effect of longitudinal relaxation of ligand protons on saturation transfer difference (STD) was investigated by using a known binding system, dihydrofolate reductase and trimethoprim. The results indicate that T1 relaxation of ligand protons has a severe interference on the epitope map derived from a STD measurement. When the T1s of individual ligand protons are distinctly different, STD experiments may not give an accurate epitope map for the ligand-target interactions. Measuring the relaxation times prior to mapping is strongly advised. A saturation time shorter than T1s is suggested for improving the potential epitope map. Reduction in temperature was seen to enhance the saturation efficiency in small to medium size targets.
Bioorganic & Medicinal Chemistry Letters | 1995
Stephen W. Kaldor; Marlys Hammond; Bruce A. Dressman; Jean M. Labus; Frederick W. Chadwell; Allen D. Kline; Beverly A. Heinz
Peptide aldehydes have been synthesized and evaluated as inhibitors of human rhinovirus 3C protease. Those inhibitors containing a C-terminal glutamine aldehyde were prepared using newly developed methodology involving reduction of the corresponding glutarimide, which can be easily prepared from N-protected glutamine. Low molecular weight (<500) compounds with low to submicromolar inhibitory activity in both isolated enzyme and in vitro translation assays have been identified.
Current Topics in Medicinal Chemistry | 2003
Edward R. Zartler; Jiangli Yan; Huaping Mo; Allen D. Kline; Michael J. Shapiro
The drug discovery process often involves the screening of compound libraries to identify drug candidates capable of binding to target macromolecules. New approaches in biological and chemical research are driving a change in the pharmaceutical industry. Recent advances in NMR spectroscopy such as affinity NMR techniques, which detect binding of a small molecule with a “receptor”, have been shown to be valuable tools to perform rapid screening of compounds for biological activity. These NMR observable events include using relaxation, chemical shift perturbations, translational diffusion, and magnetization transfer. These one dimensional NMR methods increase both the throughput of screening and yield crucial data on the mode of binding. The practical utility of these techniques will be described.
Bioorganic & Medicinal Chemistry Letters | 1997
Matthew Joseph Fisher; Bruce P. Gunn; Cathy S. Harms; Allen D. Kline; Jeffrey Thomas Mullaney; Robert M. Scarborough; Marshall Alan Skelton; Suzane L. Um; Barbara G. Utterback; Joseph A. Jakubowski
Abstract Disubstituted 3,4-dihydroisoquinolones that contain an ether-linked benzamidine at C6 and a β-substituted aspartate mimic at C2 offer enhanced affinity for GPIIb–IIIa relative to the non-substituted isoquinolone propionate. Alkyl substituents afforded a 10-fold increase in intrinsic activity while aryl substituents yielded a 40-fold improvement.
Medizinische Monatsschrift für Pharmazeuten | 1994
Matthew Joseph Fisher; Anne Marie Happ; Joseph A. Jakubowski; Michael Dean Kinnick; Allen D. Kline; Jr John Michael Morin; Daniel Jon Sall; Marshall Alan Skelton
Journal of the American Chemical Society | 2004
Jiangli Yan; Frank Delaglio; Andreas Kaerner; Allen D. Kline; Huaping Mo; Michael J. Shapiro; Tim A. Smitka; Gregory A. Stephenson; Edward R. Zartler
Journal of Organic Chemistry | 2003
Jiangli Yan; Allen D. Kline; Huaping Mo; Michael J. Shapiro; Edward R. Zartler
Journal of Medicinal Chemistry | 1997
Matthew Fisher; Bruce P. Gunn; Cathy S. Harms; Allen D. Kline; Jeffrey Thomas Mullaney; Anne Nunes; Robert M. Scarborough; Ann E. Arfsten; Marshall Alan Skelton; Suzane L. Um; Barbara G. Utterback; Joseph A. Jakubowski
Journal of the American Chemical Society | 2002
Jiangli Yan; Allen D. Kline; Huaping Mo; Edward R. Zartler; Michael J. Shapiro