Patrick G. Holder
University of California, Berkeley
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Featured researches published by Patrick G. Holder.
Bioconjugate Chemistry | 2014
Penelope M. Drake; Aaron E. Albers; Jeanne Baker; Stefanie Bañas; Robyn M. Barfield; Abhijit Bhat; Gregory W. de Hart; Albert W. Garofalo; Patrick G. Holder; Lesley C. Jones; Romas Kudirka; Jesse M. McFarland; Wes Zmolek; David Rabuka
It is becoming increasingly clear that site-specific conjugation offers significant advantages over conventional conjugation chemistries used to make antibody–drug conjugates (ADCs). Site-specific payload placement allows for control over both the drug-to-antibody ratio (DAR) and the conjugation site, both of which play an important role in governing the pharmacokinetics (PK), disposition, and efficacy of the ADC. In addition to the DAR and site of conjugation, linker composition also plays an important role in the properties of an ADC. We have previously reported a novel site-specific conjugation platform comprising linker payloads designed to selectively react with site-specifically engineered aldehyde tags on an antibody backbone. This chemistry results in a stable C–C bond between the antibody and the cytotoxin payload, providing a uniquely stable connection with respect to the other linker chemistries used to generate ADCs. The flexibility and versatility of the aldehyde tag conjugation platform has enabled us to undertake a systematic evaluation of the impact of conjugation site and linker composition on ADC properties. Here, we describe the production and characterization of a panel of ADCs bearing the aldehyde tag at different locations on an IgG1 backbone conjugated using Hydrazino-iso-Pictet-Spengler (HIPS) chemistry. We demonstrate that in a panel of ADCs with aldehyde tags at different locations, the site of conjugation has a dramatic impact on in vivo efficacy and pharmacokinetic behavior in rodents; this advantage translates to an improved safety profile in rats as compared to a conventional lysine conjugate.
Journal of the American Chemical Society | 2012
Patrick G. Holder; Arturo A. Pizano; Bryce L. Anderson; JoAnne Stubbe; Daniel G. Nocera
Incorporation of 2,3,6-trifluorotyrosine (F(3)Y) and a rhenium bipyridine ([Re]) photooxidant into a peptide corresponding to the C-terminus of the β protein (βC19) of Escherichia coli ribonucleotide reductase (RNR) allows for the temporal monitoring of radical transport into the α2 subunit of RNR. Injection of the photogenerated F(3)Y radical from the [Re]-F(3)Y-βC19 peptide into the surface accessible Y731 of the α2 subunit is only possible when the second Y730 is present. With the Y-Y established, radical transport occurs with a rate constant of 3 × 10(5) s(-1). Point mutations that disrupt the Y-Y dyad shut down radical transport. The ability to obviate radical transport by disrupting the hydrogen bonding network of the amino acids composing the colinear proton-coupled electron transfer pathway in α2 suggests a finely tuned evolutionary adaptation of RNR to control the transport of radicals in this enzyme.
Langmuir | 2010
Patrick G. Holder; Daniel T. Finley; Nicholas Stephanopoulos; Ross Walton; Douglas S. Clark; Matthew B. Francis
We have developed a method for integrating the self-assembling tobacco mosaic virus capsid into hydrophobic solvents and hydrophobic polymers. The capsid was modified at tyrosine residues to display an array of linear poly(ethylene glycol) chains, allowing it to be transferred into chloroform. In a subsequent step, the capsids could be transferred to a variety of hydrophobic solvents, including benzyl alcohol, o-dichlorobenzene, and diglyme. The thermal stability of the material against denaturation increased from 70 °C in water to at least 160 °C in hydrophobic solvents. With a view toward material fabrication, the polymer-coated TMV rods were also incorporated into solid polystyrene and thermally cast at 110 °C. Overall, this process significantly expands the range of processing conditions for TMV-based materials, with the goal of incorporating these templated nanoscale systems into conductive polymer matrices.
Proceedings of the National Academy of Sciences of the United States of America | 2012
Arturo A. Pizano; Daniel A. Lutterman; Patrick G. Holder; Thomas S. Teets; JoAnne Stubbe; Daniel G. Nocera
Photochemical radical initiation is a powerful tool for studying radical initiation and transport in biology. Ribonucleotide reductases (RNRs), which catalyze the conversion of nucleotides to deoxynucleotides in all organisms, are an exemplar of radical mediated transformations in biology. Class Ia RNRs are composed of two subunits: α2 and β2. As a method to initiate radical formation photochemically within β2, a single surface-exposed cysteine of the β2 subunit of Escherichia coli Class Ia RNR has been labeled (98%) with a photooxidant ([Re ] = tricarbonyl(1,10-phenanthroline)(methylpyridyl)rhenium(I)). The labeling was achieved by incubation of S355C-β2 with the 4-(bromomethyl)pyridyl derivative of [Re] to yield the labeled species, [Re]-S355C-β2. Steady-state and time-resolved emission experiments reveal that the metal-to-ligand charge transfer (MLCT) excited-state 3[Re ]∗ is not significantly perturbed after bioconjugation and is available as a phototrigger of tyrosine radical at position 356 in the β2 subunit; transient absorption spectroscopy reveals that the radical lives for microseconds. The work described herein provides a platform for photochemical radical initiation and study of proton-coupled electron transfer (PCET) in the β2 subunit of RNR, from which radical initiation and transport for this enzyme originates.
Journal of the American Chemical Society | 2013
Arturo A. Pizano; Lisa Olshansky; Patrick G. Holder; JoAnne Stubbe; Daniel G. Nocera
Substrate turnover in class Ia ribonucleotide reductase (RNR) requires reversible radical transport across two subunits over 35 Å, which occurs by a multistep proton-coupled electron-transfer mechanism. Using a photooxidant-labeled β2 subunit of Escherichia coli class Ia RNR, we demonstrate photoinitiated oxidation of a tyrosine in an α2:β2 complex, which results in substrate turnover. Using site-directed mutations of the redox-active tyrosines at the subunit interface, Y356F(β) and Y731F(α), this oxidation is identified to be localized on Y356. The rate of Y356 oxidation depends on the presence of Y731 across the interface. This observation supports the proposal that unidirectional PCET across the Y356(β)-Y731(α)-Y730(α) triad is crucial to radical transport in RNR.
Bioconjugate Chemistry | 2007
Ernest W. Kovacs; Jacob M. Hooker; Dante W. Romanini; Patrick G. Holder; Katherine E. Berry; Matthew B. Francis
Angewandte Chemie | 2007
Patrick G. Holder; Matthew B. Francis
Chemistry & Biology | 2015
Romas Kudirka; Robyn M. Barfield; Jesse M. McFarland; Aaron E. Albers; Gregory W. de Hart; Penelope M. Drake; Patrick G. Holder; Stefanie Bañas; Lesley C. Jones; Albert W. Garofalo; David Rabuka
Chemical Science | 2015
David Y. Song; Arturo A. Pizano; Patrick G. Holder; JoAnne Stubbe; Daniel G. Nocera
Archive | 2007
Matthew B. Francis; Jacob M. Hooker; Ernest W. Kovacs; Dante W. Romanini; Patrick G. Holder; Katherine E. Berry