PubMed · 8560247
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C F Bennett. 1996-01-26. Antisense research.. https://pubmed.ncbi.nlm.nih.gov/8560247/
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An analogue of the human granulocyte-macrophage colony-stimulating factor (hGM-CSF), hGM-CSF(13-27)-Gly-(75-87) was synthesized by solid phase methodology. This analogue was designed to comprise helices A and C of the native growth factor, linked by a glycine bridge. Helices A and C form half of a four-helix bundle motif in the crystal structure of the native factor and are involved in the interaction with alpha- and beta-chains of the heterodimeric receptor. A conformational analysis of the synthetic analogue by CD, two-dimensional nmr spectroscopy, and molecular dynamics calculations is reported. The analogue is in a random structure in water and assumes a partially alpha-helical conformation in a 1 : 1 trifluoroethanol/water mixture. The helix content in this medium is approximately 70%. By 2D-nmr spectroscopy, two helical segments were identified in the sequences corresponding to helices A and C. In addition to medium- and short-range NOESY connectivities, a long-range cross peak was found between the Cbeta proton of Val(16) and NH proton of His(87) (using the numbering of the native protein). Experimentally derived interproton distances were used as restraints in molecular dynamics calculations, utilizing the x-ray coordinates as the initial structure. The final structure is characterized by two helical segments in close spatial proximity, connected by a loop region. This structure is similar to that of the corresponding domain in the x-ray structure of the native growth factor in which helices A and C are oriented in an antiparallel fashion. The N-terminal residues Gly-Pro of helix C are involved in an irregular turn connecting the two helical segments. As a consequence, helix C is appreciably shifted and slightly rotated with respect to helix A compared to the x-ray structure of the native growth factor. These small differences in the topology of the two helices could explain the lower biological activity of this analogue with respect to that of the native growth factor.
Rigid benzolactam P3-P2 dipeptide mimics were designed and prepared as potential inhibitors of blood coagulation factor Xa. Methoxy substitution of the tetrahydrobenzazepinone scaffold led to potent and selective inhibitors. The synthesis and biological activities of these derivatives are reported herein.
Reporter gene technology is widely used to monitor the cellular events associated with signal transduction and gene expression. Based upon the splicing of transcriptional control elements to a variety of reporter genes (with easily measurable phenotypes), it "reports" the effects of a cascade of signalling events on gene expression inside cells. The principal advantage of these assays is their high sensitivity, reliability, convenience, and adaptability to large-scale measurements. This review summarises the current status of reporter gene technology including its role in monitoring gene transfer and expression and its development as a biological screen. With the advances in this technology and in detection methods, it is likely that luciferase and green fluorescent protein will become increasingly popular for the non-invasive monitoring of gene expression in living tissues and cells. Such techniques will be important in defining the molecular events associated with gene transcription, which has implications for our understanding of the molecular basis of disease and will influence our approach to gene therapy and drug development.