Breaking the Shackles of the Genetic Code: Engineering Retroviral Proteases Through Total Chemical Synthesis
Since early this century one of the fundamental goals of organic chemistry has been to understand the molecular basis of enzyme action (1). These protein molecules are the machines of the cell, catalyzing essentially all of the chemical reactions in the biological world. The action of enzymes is characterized by extraordinary specificity and by the ability to effect, in aqueous solvent and at normal temperatures, chemical transformations that are otherwise imperceptibly slow. Early approaches to the study of enzymes involved the laborious and painstaking isolation of pure molecules from biological sources, such as tissue homogenates. Only indirect methods, such as selective chemical modification of amino acid side chains, could be used to study the functional imperatives of the protein molecule itself. Consequently, much more was known about the (usually low MW) substrates than about enzymes themselves.
KeywordsEnzyme Molecule Feline Immunodeficiency Virus Solid Phase Peptide Synthesis Aspartyl Proteinase Peptide Segment
Unable to display preview. Download preview PDF.
- 1.E. Fischer (1906), quoted in “Molecules and Life”, J.S. Fruton, Wiley-Interscience, New York, 1972, pp. 112–113Google Scholar
- 1b.E. Fischer, “Molecules and Life”, J.S. Fruton, Wiley-Interscience, New York, 1972, pp. 114Google Scholar
- 2.For example, see “Protein Engineering”, R.B. Freedman, R. Wetzel, eds., Current Opinion in Biotechnology, Vol. 3, Number 4 (August 1992).Google Scholar
- 10.M. Schnlzer, P. Alewood, D. Alewood, S.B.H. Kent, “In situ” neutralization protocols in Boc-chemistry solid phase peptide synthesis: rapid, high yield assembly of difficult sequences, Int.J.Pept.Prot.Res. 40, 180–193 (1992).Google Scholar
- 25.R.C. deLisle Milton, S.C.F. Milton, M. Schnlzer, S.B.H. Kent, Synthesis of proteins by chemical ligation of unprotected peptide segments: mirror-image enzyme molecules, D- and L-HIV protease analogs, Techniques in Protein Chemistry IV, Academic Press, New York, pp. 257–267 (1992).Google Scholar
- 26.M. Miller, J.K.M. Rao, S.C.F. Milton, R.C. deLisle Milton, S.B.H. Kent, Crystal structure of a synthetic D-enzyme prepared by chemical ligation, presented at the meeting of The Protein Society, San Diego, July 1993.Google Scholar
- 29.A.G. Tomasselli, W.J. Howe, T.K. Sawyer, A. Wlodawer, R.L. Heinrikson, The complexities of AIDS: an assessment of the HIV protease as a therapeutic target, Chimica Oggi pp.6–27 (May, 1991).Google Scholar