Chimeric molecules

Recombinant soluble TNF-RI-IgGl fusion protein Etanercept, Enbrel is a chimeric molecule consisting of the extracellular domain of the TNF receptor I (TNF-RI) and the Fc portion of human IgGl. Two Fc domains are bound to each other via disulfide bonds, thereby yielding dimers with two binding sites for the TNF trimer. Etanercept binds with high affinity to extracellular TNF and reduces TNF activity. Etanercept is not effective in Crohn s disease, possibly because it does not lead to destiuction of membrane TNF-a expressing cells. Indications and side effects are similar to those of Infliximab and Adalimumab. 

RECOMBINANT DNA TECHNOLOGY INVOLVES ISOLATION MANIPULATION OF DNA TO MAKE CHIMERIC MOLECULES... 

Isolation and manipulation of DNA, including end-to-end joining of sequences from very different sources to make chimeric molecules (eg, molecules containing both human and bacterial DNA sequences in a sequence-independent fashion), is the essence of recombinant DNA research. This involves several unique techniques and reagents. 

Manipulation of the DNA to change its structure, so-called genetic engineering, is a key element in cloning (eg, the construction of chimeric molecules) and can... 

Chimeric molecule A molecule (eg, DNA, RNA, protein) containing sequences derived from two different species. 

G. C.-Y. Wang and Y. Wang, The frequency of chimeric molecules as a consequence of PCR co-amplification of 16S rRNA genes from different bacterial species, Microbiology 142 107 (1996). 

A recent trend in the pharmaceutical industry has been to harness the intrinsic tissue-protective properties of NO for improving the gastric tolerance of nonsteroidal antiinflammatory drugs (NS AIDs). This trend has led to the synthesis of hybrid, chimeric molecules containing an NSAID or aspirin moiety and a NO-donor functionality [153, 154]. One such hybrid is a NO-releasing derivative of aspirin, NCX-4016. In a doubleblind, randomized, placebo-controlled gastrointestinal safety assessment in healthy subjects, NCX-4016 (400 or 800 mg twice daily for 7 days) acted like aspirin as an inhibitor of arachidonic acid-induced platelet aggregation in vitro [155]. Whether... 

After following the procedure for random chimera production, the resulting chimeric molecules will have exchanges delimited by the truncated cDNA in step b)... 

As suggested above, the presence of an N-terminal Ser or Thr in a protein can be used to generate a reactive carbonyl group. This will be at a unique site, as there is only one N-terminus per polypeptide chain. Furthermore, that site is exactly the one required for there to be contiguity of the backbone of the chimeric molecule under construction. 

In practice, then, the slow-growth technique is rather different from FEP when it comes to evaluating AE. Since each change in A is also a step in the simulation, all of the intrasolvent energy terms change in addition to the solvent-solute interaction terms. With respect to the latter terms, however, the evaluation is similar to FEP in that chimeric molecules are involved. 

Chimeric peptides are unnatural constructs consisting of bioactive compounds from at least two different peptide(s) and/or protein(s) or two sequences from different parts of the same protein. Such multifunctional peptide combinations are prepared to enhance the biological activity or selectivity of their components. New biological effects can also be achieved with the chimera. In this chapter the synthesis of three different types of chimeric peptides will be described. In a linear chimera, two peptide epitopes from different parts of glycoprotein D (gD) of herpes simplex virus (HSV) are combined. A branched chimera, built from linear peptides, consists of tuftsin oligomers with immunostimulatory activity and an epitope peptide of HSV gD. The third compound is a cyclic chimeric molecule, where a-cono-toxin GI as a host peptide is modified by the incorporation of a core epitope from HSV gD as a guest sequence. 

Vella, F., Hernandez, J.-F., Molla, A., Block, M. R., and Arlaud, G. J. (1999) Grafting an RGD motif onto an epidermal growth factor-Uke module chemical synthesis and functional characterization of the chimeric molecule. J. Pept. Res. 54, 415-426. 

Chimeric molecules composed of regions of the HIV virus receptor and immunoglobulins, dubbed immunoadhesins , are under development as therapeutics for AIDS. HIV enters its preferred host cell, the helper T lymphocyte, by interaction between the viral surface glycoprotein, gpl20 and a transmembrane... 

Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM, Deshaies RJ. Protacs chimeric molecules that target proteins to the Skpl-Cullin-F box complex for ubiquitination and degradation. Proc. Natl. Acad. Sci. U.S.A. 2001 98, 8554-8559. 

There is now a substantial literature on the synthesis and testing of chimeric molecules. These substances are each composed of at least two functional domains, such as a tissue-targeting domain and a pharmacologically active domain. One common strategy in constructing chimeric toxins is to isolate the binding domain of one toxin (e.g., diphtheria toxin) and attach this to the poisoning domain of another (e.g., ricin). This chimeric molecule attaches only to cells that have the diphtheria toxin receptor, and it expresses only the intracellular effects of ricin. 

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