Morten P. Meldal - Career

Career

Meldal first received a B.S. degree and then a Ph.D. degree in Chemical Engineering from TCU; his Ph.D. work focused on the synthetic chemistry of oligosaccharides. From 1983-1988 he worked as independent research associate in organic chemistry at TCU and University of Copenhagen. He then (1985–1986) performed postdoctoral work at Cambridge University; he was a postdoctoral research associate at the Medical Research Council Center, Laboratory of Molecular Biology. In 1996 he was appointed adjunct professor at Danish Technical University. Since 1998 he has led the synthesis group in the Department of Chemistry of the Carlsberg Laboratory and since 1997 head of the SPOCC Center.

Throughout his career Meldal has had an outstanding influence on contemporary methodology in peptide- and combinatorial chemistry and has always contributed with innovative and practical solutions to the currently most pressing general problems in these scientific fields. In many instances the solid phase methodologies developed by Meldal are years ahead of time. There is a number of contributions that merits nomination.

The highly cited Cu-catalyzed chemical “click” ligation (cycloaddition) of acetylenes and azides currently widely used in peptide and protein conjugations, in polymers and in materials sciences was presented first by Meldal at APS 2001. His group also showed this reaction to be completely orthogonal to the majority of functional group chemistries and that the triazole formed could act both as a convenient substitute for disulfide bonds in peptides and as a peptide bond surrogate.

PEG based resins, PEGA, SPOCC, POEPOP, ULTRAMINE and other acronyms stands for well recognized solid supports (patented) originating in Meldal’s group that have facilitated the merger of solid phase peptide- and peptide-organic chemistry with solid phase chemical biology and protein chemistry. These resins can be tailored for a particular purpose and are unique in their amphipatic nature that provides unprecedented swelling behavior in both non-polar organic solvents and aqueous buffers. He developed physical methods to study the diffusion of peptides and proteins in polymer beads. A particularly useful property of the PEG-based resins was their use for on-bead MAS NMR and was demonstrated by structural analysis of resin bound glycopeptides.

In the early part of his career he developed several technologically advanced techniques and instruments for peptide synthesis. This include the carousel amino acid delivery system (patented) used in an ABI sunthesizer and the first real time on resin spectrophotometric monitoring (patented) of the peptide coupling reactions using the yellow color of DHBT-OH when deprotonated by residual amino groups. This technique allowed the first real time solid phase kinetics in peptide synthesis to be performed. He developed the multiple column synthesis (patented in 1988) used extensively until today by instrument companies for both peptide and organic synthesis instrumentation. He also developed practical instrumentation for assembly of large split mix libraries.

More recently Meldal has developed the first practical optical encoding technique for beaded solid supports for tracking chemical identity during synthesis and screening at high rate and with a large encoding potential, particularly in combinatorial chemistry. The technique is currently in industrial application for the rapid identification of ligands for large scale purification of pharmaceutical proteins (Patented).

Meldal developed a large range of chemical technologies based on temporary protection schemes for glycopeptide synthesis including all known types of N, O and C-linked glycopeptides. These were used in e. g. characterization of the immunological response to cancer related mucins. A concept of using template based glycopeptide mimetics for mimicking function of complex carbohydrate structures was developed and the mimetics employed in biochemical studies (Patented).

Meldal has developed many fluorescence based screening techniques including solid phase protease assays for both determination of specificity and for inhibitor development based on FRET techniques (Patented). This type of assay is currently forming a chemical basis for a large EU-research program on characterization of the mammalian proteases. He developed solid phase synthesis of combinatorial libraries of peptides containing phosphinic acid as transition state analogs and identified nanomolar selective inhibitors for metalloproteases involved in osteoclast migration towards the control of osteoporosis.

In his work during the last decade he has focused on the merger of organic chemistry and peptide chemistry on solid support and has devised a large range novel methods based on the highly specific generation of N-acyl iminium ions involving backbone or sidechain amides to yield complex large heterocyclic systems from peptides upon intramolecular cascade reaction with C-, N-, O- and S-nucleophiles. Combinatorial libraries of these compounds was generated and screened for GPCR active substances in cell-based on-bead screening using functionalized PEGA supports.

He developed the concept of organozymes, peptide-organic molecules that fold around transition metals and chelate these through phosphines, carbenes and heterocycles and act as enzyme like chiral catalysts on solid support. Along the same lines he developed peptide based cage like receptors that recognize e. g. sugars water.

He also introduced a solid phase synthesis technique based on protection of the amine as azide that allowed clean activation as acid chloride and synthesis of highly sterically hindered oligomers of alfa-dialkyl and alfa-diaryl amino acids not accessible through other methods. Furthermore, the solid phase assembly of peptides using the azide protection facilitated orthogonal chemistries required for glycopeptide assembly.

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