Synthesis at the interface of chemistry and biology

Abstract

As the focus of synthesis increasingly shifts from its historical emphasis on molecular structure to function, improved strategies are clearly required for the generation of molecules with defined physical, chemical, and biological properties. In contrast, living organisms are remarkably adept at producing molecules and molecular assemblies with an impressive array of functions - from enzymes and antibodies to the photosynthetic center. Thus, the marriage of Nature's synthetic strategies, molecules, and biosynthetic machinery with more traditional synthetic approaches might enable the generation of molecules with properties difficult to achieve by chemical strategies alone. Here we illustrate the potential of this approach and overview some opportunities and challenges in the coming years.

Figure 1

Synthetic molecules that sequence specifically bind duplex DNA based on specific hydrogen bonding interactions, much like transcriptional repressors (Courtesy of Peter Dervan).

Figure 2

Modular thiotemplated assembly lines for the biosynthesis of vancomycin (Courtesy Christopher Walsh).

Figure 3

Protein biosynthesis with an expanded genetic code (Courtesy Ambrx).

Figure 4

An expanding genetic code – examples of unnatural amino acids that have been genetically encoded in prokaryotic or eukaryotic organisms.

Figure 5

A. Metal-ion binding amino acid HQ-Ala and crystal structure of TM0665 Phe22 HQAla mutant. B. Fluorescent amino acid Prodan-Ala and fluorescence changes of an Asn160 Prodan-Ala mutant of Glutamine Binding Protein upon addition of Gln.

Figure 6

Substitution of the immunogenic amino acid p-nitrophenylalanine for Tyr86 in murine TNF-α and subsequent vaccination leads to a robust T-cell driven immune response which cross reacts with wildtype TNF-α and protects mice from LPS challenge.

Figure 7

Combinatorial association of V, D and J genes with recombination imprecision and subsequent somatic hypermutation during affinity maturation results in an enormous antibody repertoire capable of binding virtually any foreign molecule.

Figure 8

A catalytic antibody with broad substrate specificity that catalyzes aldol reactions through covalent catalysis.

Figure 9

X-ray crystal structure of the Michaelis complex of the strained mesoporphyrin substrate in a ferrochelatase antibody active site.

Figure 10

Structural plasticity of a germline antibody that binds N-methylmesoporphyrin (NMP); somatic mutations during affinity maturation lock the optimal active site conformation.

Figure 11

A library of novel luminescent molecules generated by laser ablation of metal oxides through a series of physical masks, under both ambient and UV irradiation.

Figure 12

Automated high throughput screening systems and chemical, genomic and protein libraries are enabling large scale, cost effective cellular screens; mechanisms should be found to make these tools available to moreacademic laboratories. (Courtesy GNF Engineering).

Figure 13

An efficient synthesis of heterocycle libraries.

Figure 14

Purmorphamine induces the selective differentiation of mesenchymal stem cells to osteoblasts by activating the Hedgehog signaling pathway.

Figure 15

(A) Stauprimide potentiates the differentiation of ES cells toward the definitive endoderm fate. (B) Mouse ES cells treated with stauprimide differentiate at high efficiency into endoderm-derived lineages, including hepatocytes (AFP, Albumin, Cyp7A1) and pancreatic precursors (Pdx1 and Ngn3). (C) Stauprimide also increases the differentiation of human ES cells into definitive endoderm.

Figure 16

Reversine reprograms myoblasts (which normally differentiate into myotubes) to precursor cells that can be differentiated into osteoblasts or adipocytes^,.

Fig 17

A kinase of interest can be genetically engineered to be selectively inhibited by an orthogonal kinase inhibitor which does not inhibit any wild-type protein kinases. The conservation of the ATP binding pocket across the kinome provides generality to the approach as the residue which must be engineered is conserved (Courtesy Kevan Shokat).

Figure 18

The template directed synthesis of libraries of macrocycles^, (Courtesy David Liu).

Scheme I