nSite-Selective, Chemical Modification of Protein at Aromatic Side Chain and Their Emergent Applications

: Site-selective chemical modification of protein side chain has probed enormous opportunities in the fundamental understanding of cellular biology and therapeutic applications. Primarily, in the field of biopharmaceutical where formulation of bioconjugates is found to be potential medicine than an individual constituent. In this regard, Lysine and Cysteine are the most widely used endogenous amino acid for these purposes. Recently, the aromatic side chain residues (Trp, Tyr, and His) that are low abundant in protein have gained more attention in therapeutic applications due to their advantages of chemical reactivity and specificity. This review discusses the site-selective bioconjugation methods for aromatic side chains (Trp, Tyr and His) and highlights the developed strategies in the last three years, along with their applications. Also, the review highlights the prevalent methods published earlier. We have examined that metal-catalyzed and photocatalytic reactions are gaining more attention for bioconjugation, though their practical operation is under development. The review has been summarized with the future perspective of protein and peptide conjugations contemplating therapeutic applications and challenges.

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Site-selective Chemical Modification of Chymotrypsin Using a Peptidyl Diphenyl 1-Amino-2-phenylethylphosphonate Derivative

Chemistry Letters ◽

10.1246/cl.130244 ◽

2013 ◽

Vol 42 (8) ◽

pp. 860-862 ◽

Cited By ~ 2

Author(s):

Shin Ono ◽

Junya Murai ◽

Takahiko Nakai ◽

Hirofumi Kuroda ◽

Yoshikazu Horino ◽

...

Keyword(s):

Chemical Modification ◽

Selective Chemical ◽

Site Selective

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Proton NMR studies of the structural and dynamical effect of chemical modification of a single aromatic side-chain in a snake cardiotoxin Relation of the structure of the putative binding site and the cytolitic activity of the toxin

Journal of Molecular Biology ◽

10.1016/0022-2836(94)90043-4 ◽

1994 ◽

Vol 243 (4) ◽

pp. 719-735 ◽

Cited By ~ 16

Author(s):

C. Roumestand ◽

B. Gilquin ◽

O. Trémeau ◽

E. Gatineau ◽

L. Mouawad ◽

...

Keyword(s):

Chemical Modification ◽

Binding Site ◽

Proton Nmr ◽

Dynamical Effect ◽

Side Chain ◽

Aromatic Side Chain ◽

Nmr Studies ◽

Putative Binding Site

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Bioconjugation – using selective chemistry to enhance the properties of proteins and peptides as therapeutics and carriers

Organic & Biomolecular Chemistry ◽

10.1039/c6ob00808a ◽

2016 ◽

Vol 14 (34) ◽

pp. 8002-8013 ◽

Cited By ~ 28

Author(s):

Smita B. Gunnoo ◽

Annemieke Madder

Keyword(s):

Chemical Modification ◽

Protein Therapeutics ◽

Wide Range ◽

Therapeutic Properties ◽

Selective Chemical ◽

Site Selective ◽

Proteins And Peptides

Both peptide and protein therapeutics are becoming increasingly important for treating a wide range of diseases. Functionalisation of theseviasite-selective chemical modification leads to enhancement of their therapeutic properties.

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Recognition Directed Site-Selective Chemical Modification of Molecularly Imprinted Polymers

Macromolecules ◽

10.1021/ma010903s ◽

2001 ◽

Vol 34 (24) ◽

pp. 8446-8452 ◽

Cited By ~ 47

Author(s):

Robert J. Umpleby ◽

Gregory T. Rushton ◽

Ripal N. Shah ◽

Andrew M. Rampey ◽

Jessica C. Bradshaw ◽

...

Keyword(s):

Chemical Modification ◽

Molecularly Imprinted Polymers ◽

Molecularly Imprinted ◽

Imprinted Polymers ◽

Selective Chemical ◽

Site Selective

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Site-selective chemical modification of chymotrypsin using peptidyl derivatives bearing optically active diphenyl 1-amino-2-phenylethylphosphonate: Stereochemical effect of the diphenyl phosphonate moiety

Biopolymers ◽

10.1002/bip.22790 ◽

2016 ◽

Vol 106 (4) ◽

pp. 521-530 ◽

Cited By ~ 2

Author(s):

Shin Ono ◽

Takahiko Nakai ◽

Hirofumi Kuroda ◽

Ryuta Miyatake ◽

Yoshikazu Horino ◽

...

Keyword(s):

Chemical Modification ◽

Optically Active ◽

Selective Chemical ◽

Site Selective

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Theoretical and experimental studies of palladium-catalyzed site-selective C(sp3)−H bond functionalization enabled by transient ligands

10.26434/chemrxiv.5717950 ◽

2017 ◽

Author(s):

Haibo Ge ◽

Lei Pan ◽

Piaoping Tang ◽

Ke Yang ◽

Mian Wang ◽

...

Keyword(s):

Bond Activation ◽

Theoretical Calculations ◽

Experimental Studies ◽

Bond Functionalization ◽

Aliphatic Ketones ◽

Site Selectivity ◽

Mechanistic Investigation ◽

Palladium Catalyzed ◽

Metal Catalyzed ◽

Site Selective

Transition metal-catalyzed selective C–H bond functionalization enabled by transient ligands has become an extremely attractive topic due to its economical and greener characteristics. However, catalytic pathways of this reaction process on unactivated sp3 carbons of reactants have not been well studied yet. Herein, detailed mechanistic investigation on Pd-catalyzed C(sp3)–H bond activation with amino acids as transient ligands has been systematically conducted. The theoretical calculations showed that higher angle distortion of C(sp2)-H bond over C(sp3)-H bond and stronger nucleophilicity of benzylic anion over its aromatic counterpart, leading to higher reactivity of corresponding C(sp3)–H bonds; the angle strain of the directing rings of key intermediates determines the site-selectivity of aliphatic ketone substrates; replacement of glycine with β-alanine as the transient ligand can decrease the angle tension of the directing rings. Synthetic experiments have confirmed that β-alanine is indeed a more efficient transient ligand for arylation of β-secondary carbons of linear aliphatic ketones than its glycine counterpart.

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Faculty Opinions recommendation of Single-Site Labeling of Native Proteins Enabled by a Chemoselective and Site-Selective Chemical Technology.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.734251807.793555750 ◽

2019 ◽

Author(s):

Scott Silverman

Keyword(s):

Chemical Technology ◽

Single Site ◽

Native Proteins ◽

Selective Chemical ◽

Site Selective

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Rational Generation of Lasso Peptides Based on Biosynthetic Gene Mutations and Site-Selective Chemical Modifications

Chemical Science ◽

10.1039/d1sc02695j ◽

2021 ◽

Author(s):

Tan Liu ◽

Xiaojie Ma ◽

Jiahui Yu ◽

Wensheng Yang ◽

guiyang wang ◽

...

Keyword(s):

Natural Products ◽

Gene Mutations ◽

Proteolytic Degradation ◽

Biosynthetic Gene ◽

Chemical Modifications ◽

Lasso Peptides ◽

Selective Chemical ◽

Site Selective

Lasso peptides are a unique family of natural products whose structures feature a specific threaded fold, which confers these peptides the resistance to thermal and proteolytic degradation. This stability gives...

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Synthesis of Substituted -N-(5-((7-Methyl-2-Oxo-2H-Chromen-4-yl)-Methyl)-1,3,4-Thiadiazol-2-yl)-Benzamide Derivatives Using TBTU As Coupling Agent And Their Evaluation For Anti Tubercular Activity

Letters in Organic Chemistry ◽

10.2174/1570178618666210602160849 ◽

2021 ◽

Vol 18 ◽

Author(s):

Monika Kakadiya ◽

Yunus Pasha ◽

Malleshappa Noolvi ◽

Ashish Patel

Keyword(s):

Antitubercular Activity ◽

Side Chain ◽

Antitubercular Agents ◽

Facile Synthesis ◽

Aromatic Side Chain ◽

Reaction Conditions ◽

Coupling Reagent ◽

H37rv Strain ◽

Benzamide Derivatives

: Tuberculosis remains a highly infectious disease across the world. In the identification of new antitubercular agents, coumarin clubbed thiadiazole amides have been synthesized and evaluated for in vitro antitubercular activity. Due to the growing concern about chemicals and their impact on the environment, greener and faster reaction conditions needed to be incorporated. Therefore, we used TBTU as a coupling reagent for efficient and facile synthesis of substituted-N-(5-((7-methyl-2-oxo-2H-chromes-4-yl)-methyl)-1,3, 4 - thiadiazol-2-yl)-benzamide 4a-j with good yields up to 95% in mild reaction condition. All the synthesized compounds were evaluated in vitro for antitubercular activity against the H37Rv strain of M.Tuberculosis. Compounds 4c, 4f, and 4j were found active at 25 µg/mL against M. tb H37Rv. Electron withdrawing substituents present on aromatic side-chain showed promising anti-tubercular activity.

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