Nonconventional catalysts for isotactic propene polymerization in solution developed by using high-throughput-screening technologies.
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Journal Article↗
Biomedical subjects
Vince Murphy
Publications and source records attributed to Vince Murphy.
Refolding, purification, and crystallization of apical membrane antigen 1 from Plasmodium falciparum.
Extracellular domains of malaria antigens almost invariably contain disulphide linkages but lack N- and O-linked glycosylation. The best practical approach to generating recombinant extracellular Plasmodium proteins is not established and the problems encountered when using a bacterial expression/refolding approach are discussed in detail. Limited proteolysis experiments were used to identify a relatively non-flexible core region of the Plasmodium falciparum protein apical membrane antigen 1 (AMA1), and refolding/purification was used to generate two fragments of AMA1. Several chromatographically distinct AMA1 variants were identified that are presumably differentially refolded proteins. One of these AMA1 preparations proved to be crystallizable and generated two crystal forms that diffracted X-rays to 2 A resolution.
Animals↗
Allelic polymorphisms in apical membrane antigen-1 are responsible for evasion of antibody-mediated inhibition in Plasmodium falciparum.
Apical membrane antigen-1 (AMA-1) is a target of antibodies that inhibit invasion of Plasmodium falciparum into human erythrocytes and is a candidate for inclusion in a malaria vaccine. We have identified a line of P. falciparum (W2mef) less susceptible to anti-AMA1 antibodies raised to the protein from a heterologous parasite line (3D7). We have constructed transgenic P. falciparum expressing heterologous AMA-1 alleles. In vitro invasion assays show that these transgenic parasites differ from parental lines in susceptibility to inhibitory antibodies, providing direct evidence that sequence polymorphisms within AMA-1 are responsible for evasion of immune responses that inhibit parasite invasion. We also generated a parasite line that would express a chimeric AMA-1 protein, in which highly polymorphic residues within domain 1 were exchanged. Inhibition assays suggest that these residues are not sufficient for inhibition by invasion-blocking antibodies. This study is the first to use P. falciparum allelic exchange to examine the relationship between genetic diversity and susceptibility to protective antibodies. The findings have important implications for the development of an AMA-1-based malaria vaccine.
Alleles↗
A fully integrated high-throughput screening methodology for the discovery of new polyolefin catalysts: discovery of a new class of high temperature single-site group (IV) copolymerization catalysts.
For the first time, new catalysts for olefin polymerization have been discovered through the application of fully integrated high-throughput primary and secondary screening techniques supported by rapid polymer characterization methods. Microscale 1-octene primary screening polymerization experiments combining arrays of ligands with reactive metal complexes M(CH(2)Ph)(4) (M = Zr, Hf) and multiple activation conditions represent a new high-throughput technique for discovering novel group (IV) polymerization catalysts. The primary screening methods described here have been validated using a commercially relevant polyolefin catalyst, and implemented rapidly to discover the new amide-ether based hafnium catalyst [eta(2)-(N,O)[bond](2-MeO[bond]C(6)H(4))(2,4,6-Me(3)C(6)H(2))N]Hf(CH(2)Ph)(3) (1), which is capable of polymerizing 1-octene to high conversion. The molecular structure of 1 has been determined by X-ray diffraction. Larger scale secondary screening experiments performed on a focused 96-member amine-ether library demonstrated the versatile high temperature ethylene-1-octene copolymerization capabilities of this catalyst class, and led to significant performance improvements over the initial primary screening discovery. Conventional one gallon batch reactor copolymerizations performed using selected amide-ether hafnium compounds confirmed the performance features of this new catalyst class, serving to fully validate the experimental results from the high-throughput approaches described herein.
Journal Article↗
High-throughput approaches to catalyst discovery.
High-throughput synthesis and screening approaches to catalyst discovery and optimization are systematically changing the way in which catalyst research is conducted. Increased rates of innovation, cost effectiveness, improved intellectual property, reduced time to market and an improved probability of success are some of the attractive features that demand consideration. Advances made over the past few years reveal that any initial skepticism is waning, and high-throughput approaches to catalyst discovery are now being implemented broadly in industrial and academic laboratories.
Catalysis↗
Triple tandem catalyst mixtures for the synthesis of polyethylenes with varying structures.
Tandem catalysis in a single medium presents challenges and opportunities for creating novel synthetic protocols. Thus far, only two homogeneous catalysts have been used in tandem. Herein, we report that it is possible to coordinate the action of three well-defined homogeneous catalysts to produce a wide range of branched polyethylenes from a single monomer. Thus, ([(eta(5)-C(5)Me(4))SiMe(2)(eta(1)-NCMe(3))]TiMe)(MeB(C(6)F(5))(3)) (1), [(C(6)H(5))(2)PC(6)H(4)C(OB(C(6)F(5))(3))O-kappa(2)P,O]Ni(eta(3)-CH(2)C(6)H(5)) (2), and ((H(3)C)C[N(C(6)H(5))]C[O-B(C(6)F(5))(3)][N(C(6)H(5))]-kappa(2)N,N)Ni(eta(3)-CH(2)C(6)H(5)) (3) react with ethylene to produce branched polyethylene with structures that cannot be obtained using a single- or a two-component catalyst combination. The properties of the polyethylene depend on the ratio of the three catalysts. High-throughput screening techniques proved essential for optimizing reaction conditions and for probing how the catalyst composition influences the polymer properties.
Journal Article↗
High-throughput approaches for the discovery and optimization of new olefin polymerization catalysts.
The discovery of new olefin polymerization catalysts is currently a time-intensive trial-and-error process with no guarantee of success. A fully integrated high-throughput screening workflow for the discovery of new catalysts for polyolefin production has been implemented at Symyx Technologies. The workflow includes the design of the metal-ligand libraries using custom-made computer software, automated delivery of metal precursors and ligands into the reactors using a liquid-handling robot, and a rapid primary screen that serves to assess the potential of each metalligand-activator combination as an olefin polymerization catalyst. "Hits" from the primary screen are subjected to secondary screens using a 48-cell parallel polymerization reactor. Individual polymerization reactions are monitored in real time under conditions that provide meaningful information about the performance capabilities of each catalyst. Rapid polymer characterization techniques support the primary and secondary screens. We have discovered many new and interesting catalyst classes using this technology.
Journal Article↗