Glycoproteins are among nature's most important and wide-spread bioactive agents, serving to regulate a wide range of essential biological functions. In spite of this, their structures can be simplified to give four basic """"""""cores"""""""" which serves as backbones to which other sugars can be added in order to achieve the observed biological specificities. Our knowledge of their specificities is limited by the fact that laboratory preparative routes are not readily available. These problems of laboratory preparation, take on added significance at the present time in view of the frantic search for an AIDS vaccine in which many medicinal chemists are engaged. To this end investigators at Duke University Medical Center have focussed attention on the envelope glycoprotein (gp-120) of the HIV virus, and their discussions with us have identified the high-mannose-type of glycoprotein as a primary target for synthetic conquest. A survey of the literature suggests that the major problems confronting the syntheses of high-mannose glycoproteins can be divided into four categories: 1) problems associated with the assembly of the oligosaccharide moiety; 2) the controlled creation of the troublesome beta-linkage between mannose and the N-acetylglucosamine residues; 3) the installation of the ubiquitous asparagine residue at the anomeric center, and 4) the elaboration of the peptide chain. The development of strategies for tackling these four objectives is outlined. Our approach depends heavily on the chemistry of n-pentenyl glycosides as a novel method for activation of the anomeric center towards various coupling reactions. Professor Tom Matthews of the Duke University Medical Center will supply us with any peptides needed (see item 4 above). Although our development of synthetic strategies will be focussed on the gp-120 vaccine candidate, it should be emphasized that the methodology to be explored should be applicable to a wide variety of glycoproteins. The existence of core structures, as described above, ensures that our methodology will not be confined to a given target.
| Debenham, J S; Debenham, S D; Fraser-Reid, B (1996) N-Tetrachlorophthaloyl (TCP) for ready protection/deprotection of amino sugar glycosides. Bioorg Med Chem 4:1909-18 |
