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Start Over Author "Rickert, Keith" Topic dimerization
2 results on '"Rickert, Keith"'

1. A Diene‐Containing Noncanonical Amino Acid Enables Dual Functionality in Proteins: Rapid Diels–Alder Reaction with Maleimide or Proximity‐Based Dimerization

Author

St. Amant, Andre H, Huang, Fengying, Lin, Jia, Rickert, Keith, Oganesyan, Vaheh, Lemen, Daniel, Mao, Shenlan, Harper, Jay, Marelli, Marcello, Wu, Herren, Gao, Changshou, de Alaniz, Javier Read, and Christie, R James

Subjects
Organic Chemistry, Chemical Sciences, Biotechnology, Immunization, Alkadienes, Amino Acids, Cycloaddition Reaction, Dimerization, Humans, Immunoglobulin Fc Fragments, Immunoglobulin G, Maleimides, Models, Molecular, Molecular Structure, antibody-drug conjugate, Diels-Alder reaction, diene, non-canonical amino acid, proximity-driven reaction, Chemical sciences
Abstract

Here, we describe a diene-containing noncanonical amino acid (ncAA) capable of undergoing fast and selective normal electron-demand Diels-Alder (DA) reactions following its incorporation into antibodies. A cyclopentadiene derivative of lysine (CpHK) served as the reactive handle for DA transformations and the substrate for genetic incorporation. CpHK incorporated into antibodies with high efficiency and was available for maleimide conjugation or self-reaction depending on position in the amino acid sequence. CpHK at position K274 reacted with the maleimide drug-linker AZ1508 at a rate of ≈79 m-1  s-1 to produce functional antibody-drug conjugates (ADCs) in a one-step process. Incorporation of CpHK at position S239 resulted in dimerization, which covalently linked antibody heavy chains together. The diene ncAA described here is capable of producing therapeutic protein conjugates with clinically validated and widely available maleimide compounds, while also enabling proximity-based stapling through a DA dimerization reaction.

Published
2019

2. A Diene-Containing Noncanonical Amino Acid Enables Dual Functionality in Proteins: Rapid Diels-Alder Reaction with Maleimide or Proximity-Based Dimerization

Author

St Amant, Andre H, Huang, Fengying, Lin, Jia, Rickert, Keith, Oganesyan, Vaheh, Lemen, Daniel, Mao, Shenlan, Harper, Jay, Marelli, Marcello, Wu, Herren, Gao, Changshou, Read de Alaniz, Javier, and Christie, R James

Subjects
Molecular Structure, Cycloaddition Reaction, Organic Chemistry, Molecular, non-canonical amino acid, diene, Immunoglobulin Fc Fragments, antibody-drug conjugate, Maleimides, Alkadienes, Models, Immunoglobulin G, Chemical Sciences, Humans, Amino Acids, Diels-Alder reaction, Dimerization, proximity-driven reaction
Abstract

Here, we describe a diene-containing noncanonical amino acid (ncAA) capable of undergoing fast and selective normal electron-demand Diels-Alder (DA) reactions following its incorporation into antibodies. A cyclopentadiene derivative of lysine (CpHK) served as the reactive handle for DA transformations and the substrate for genetic incorporation. CpHK incorporated into antibodies with high efficiency and was available for maleimide conjugation or self-reaction depending on position in the amino acid sequence. CpHK at position K274 reacted with the maleimide drug-linker AZ1508 at a rate of ≈79 m-1 s-1 to produce functional antibody-drug conjugates (ADCs) in a one-step process. Incorporation of CpHK at position S239 resulted in dimerization, which covalently linked antibody heavy chains together. The diene ncAA described here is capable of producing therapeutic protein conjugates with clinically validated and widely available maleimide compounds, while also enabling proximity-based stapling through a DA dimerization reaction.

Published
2019

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