Reprogramming natural proteins using unnatural amino acids

Adhikari, Anup; Bhattarai, Bibek Raj; Aryal, Ashika; Thapa, Niru; Kc, Puja; Adhikari, Ashma; Maharjan, Sushila; Chanda, Prem B.; Regmi, Bishnu P.; Parajuli, Niranjan

doi:10.1039/d1ra07028b

Cited by 35 publications

(29 citation statements)

References 135 publications

(197 reference statements)

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“…SAR444245 is currently in Phase 2 clinical trials and uses a non-natural N 6 -(2-azidoethoxy)-carbonyl-L-lysine amino acid for site-selective conjugation to dibenzocyclooctyne-functionalized PEG. While the methods for incorporating non-natural amino acids into protein sequences are out of scope in this review, readers are referred to several recent reviews on this topic [ 258 , 259 ].…”

Section: Protein/peptide Therapeutics That Are Enhanced Through Chemi...mentioning

confidence: 99%

A Review of Protein- and Peptide-Based Chemical Conjugates: Past, Present, and Future

Holz¹,

Darwish²,

Tesar³

et al. 2023

Pharmaceutics

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Over the past few decades, the complexity of molecular entities being advanced for therapeutic purposes has continued to evolve. A main propellent fueling innovation is the perpetual mandate within the pharmaceutical industry to meet the needs of novel disease areas and/or delivery challenges. As new mechanisms of action are uncovered, and as our understanding of existing mechanisms grows, the properties that are required and/or leveraged to enable therapeutic development continue to expand. One rapidly evolving area of interest is that of chemically enhanced peptide and protein therapeutics. While a variety of conjugate molecules such as antibody–drug conjugates, peptide/protein–PEG conjugates, and protein conjugate vaccines are already well established, others, such as antibody–oligonucleotide conjugates and peptide/protein conjugates using non-PEG polymers, are newer to clinical development. This review will evaluate the current development landscape of protein-based chemical conjugates with special attention to considerations such as modulation of pharmacokinetics, safety/tolerability, and entry into difficult to access targets, as well as bioavailability. Furthermore, for the purpose of this review, the types of molecules discussed are divided into two categories: (1) therapeutics that are enhanced by protein or peptide bioconjugation, and (2) protein and peptide therapeutics that require chemical modifications. Overall, the breadth of novel peptide- or protein-based therapeutics moving through the pipeline each year supports a path forward for the pursuit of even more complex therapeutic strategies.

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Section: Protein/peptide Therapeutics That Are Enhanced Through Chemi...mentioning

confidence: 99%

A Review of Protein- and Peptide-Based Chemical Conjugates: Past, Present, and Future

Holz¹,

Darwish²,

Tesar³

et al. 2023

Pharmaceutics

View full text Add to dashboard Cite

show abstract

“…Target residues within the aaRS active site are mutated to generate libraries, which are then subjected to a two-step screening process over multiple cycles to select mutant aaRS/tRNAs that accept only the desired nnAAs. Based on this method, an increasing number of orthologous pairs have been developed, enabling more than 200 nnAAs to be successfully incorporated into proteins [ 22 ]. Using Pyrrolysyl-tRNA synthetase as an example, its high tolerance to substrate side chains and low selectivity towards α-amine and tRNA anticodons allow it to be relatively easily evolved to accommodate more nnAAs or α-hydroxy acids into proteins [ 23 ].…”

Section: Orthologous Aminoacyl-trna Synthetase–trna Pairs: Key For Th...mentioning

confidence: 99%

Engineering of enzymes using non-natural amino acids

Dalby

2022

Bioscience Reports

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In enzyme engineering, the main targets for enhancing properties are enzyme activity, stereoselective specificity, stability, substrate range, and the development of unique functions. With the advent of genetic code extension technology, non-natural amino acids (nnAAs) are able to be incorporated into proteins in a site-specific or residue-specific manner, which breaks the limit of 20 natural amino acids for protein engineering. Benefitting from this approach, numerous enzymes have been engineered with nnAAs for improved properties or extended functionality. In this review, we focus on applications and strategies for using nnAAs in enzyme engineering. Notably, approaches to computational modelling of enzymes with nnAAs are also addressed. Finally, we discuss the bottlenecks that currently need to be addressed in order to realise the broader prospects of this genetic code extension technique.

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“…[6] Because of the growing interest in chemically modified peptides containing UAAs, most efforts have been focusing on two main strategies: 1) the development of novel synthetic protocols for UAAs for use in solid and liquid phase peptide assemblies and 2) late-stage functionalization (LSF) of peptides. [7][8][9] As a result of recent advances in deaminative strategies employing pyridinium salts, often referred to as Katritzky salts, a variety of radical alkylation procedures were developed. [10] Indeed, the use of Katritzky salts intermediates provides a new suite in selective radical alkylation of amino acids and peptides using primary amines as precursors.…”

Section: Introductionmentioning

confidence: 99%

Katritzky Salts for the Synthesis of Unnatural Amino Acids and Late‐Stage Functionalization of Peptides

2023

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Peptide drug discovery often benefits from the large structural diversity permitted by unnatural amino acids (UAAs). Indeed, numerous approved peptide drugs include UAAs in their sequences. Therefore, innovative chemical approaches either to synthesize UAAs or to allow late‐stage functionalization of peptides are emerging themes in peptide drug discovery. Thanks to the recent advances in deaminative strategies using alkylpyridiniums salts, often referred to as Katritzky salts, a variety of radical alkylation methods have been developed. In recent years the use of Katritzky salts have become popular in peptide chemistry due to their ease of preparation from a primary amine, which is a predominant functional group in amino acids. This review highlights the progress that has been made by using Katritzky salts in the synthesis of UAAs, late‐stage peptide functionalization, and peptide macrocyclization.

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Reprogramming natural proteins using unnatural amino acids

Abstract: Incorporation of unnatural amino acids into protein offers wide array of applications in fundamental and applied science.

Cited by 35 publications

References 135 publications

A Review of Protein- and Peptide-Based Chemical Conjugates: Past, Present, and Future

A Review of Protein- and Peptide-Based Chemical Conjugates: Past, Present, and Future

Engineering of enzymes using non-natural amino acids

Katritzky Salts for the Synthesis of Unnatural Amino Acids and Late‐Stage Functionalization of Peptides

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