Pin28 Use of Peginterferon Alfa-2b in Chronic Hepatitis C Patients Failing Prior Therapy: A Costeffectiveness Analysis

O'Sullivan, AK; Buti, Marı́a; Delong, K; Prasad, Mahadev; Sabater, FJ; Esteban, Rafael; Weinstein, MC

doi:10.1016/s1098-3015(10)66473-x

Cited by 2 publications

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“…Protein PEGylation, which was first reported in 1979, has led to significant increases in the circulation time and reductions in the immunogenicity of protein therapeutics. As of 2011, at least 9 PEGylated protein drugs had been approved by the Food and Drug Administration (FDA) for treatment of diseases including Hepatitis C, acute lymphoblastic leukemia, and Crohn’s disease. , While PEGylation is a useful tool to hide protein based therapeutics from the immune system and to increase size to slow elimination from the body, little additional specific functionality is added by PEGylation. In recent years, targeted drug delivery and drug carriers with responsive functionality − have also been reported to improve efficacy of protein therapeutics.…”

Section: Introductionmentioning

confidence: 99%

Rational Tailoring of Substrate and Inhibitor Affinity via ATRP Polymer-Based Protein Engineering

et al. 2014

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Atom transfer radical polymerization (ATRP)-based protein engineering of chymotrypsin with a cationic polymer was used to tune the substrate specificity and inhibitor binding. Poly(quaternary ammonium) was grown from the surface of the enzyme using ATRP after covalent attachment of a protein reactive, water-soluble ATRP-initiator. This "grafting from" conjugation approach generated a high density of cationic ammonium ions around the biocatalytic core. Modification increased the surface area of the protein over 40-fold, and the density of modification on the protein surface was approximately one chain per 4 nm(2). After modification, bioactivity was increased at low pH relative to the activity of the native enzyme. In addition, the affinity of the enzyme for a peptide substrate was increased over a wide pH range. The massively cationic chymotrypsin, which included up to 2000 additional positive charges per molecule of enzyme, was also more stable at extremes of temperature and pH. Most interestingly, we were able to rationally control the binding of two oppositely charged polypeptide protease inhibitors, aprotinin and the Bowman-Birk trypsin-chymotrypsin inhibitor from Glycine max, to the cationic derivative of chymotrypsin. This study expands upon our efforts to use polymer-based protein engineering to predictably engineer enzyme properties without the need for molecular biology.

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Section: Introductionmentioning

confidence: 99%

Rational Tailoring of Substrate and Inhibitor Affinity via ATRP Polymer-Based Protein Engineering

et al. 2014

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Solid-phase synthesis of protein-polymers on reversible immobilization supports

et al. 2018

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Facile automated biomacromolecule synthesis is at the heart of blending synthetic and biologic worlds. Full access to abiotic/biotic synthetic diversity first occurred when chemistry was developed to grow nucleic acids and peptides from reversibly immobilized precursors. Protein–polymer conjugates, however, have always been synthesized in solution in multi-step, multi-day processes that couple innovative chemistry with challenging purification. Here we report the generation of protein–polymer hybrids synthesized by protein-ATRP on reversible immobilization supports (PARIS). We utilized modified agarose beads to covalently and reversibly couple to proteins in amino-specific reactions. We then modified reversibly immobilized proteins with protein-reactive ATRP initiators and, after ATRP, we released and analyzed the protein polymers. The activity and stability of PARIS-synthesized and solution-synthesized conjugates demonstrated that PARIS was an effective, rapid, and simple method to generate protein–polymer conjugates. Automation of PARIS significantly reduced synthesis/purification timelines, thereby opening a path to changing how to generate protein–polymer conjugates.

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Pin28 Use of Peginterferon Alfa-2b in Chronic Hepatitis C Patients Failing Prior Therapy: A Costeffectiveness Analysis

Cited by 2 publications

References 0 publications

Rational Tailoring of Substrate and Inhibitor Affinity via ATRP Polymer-Based Protein Engineering

Rational Tailoring of Substrate and Inhibitor Affinity via ATRP Polymer-Based Protein Engineering

Solid-phase synthesis of protein-polymers on reversible immobilization supports

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