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Related Concept Videos

Adrenergic Agonists: Chemistry and Structure-Activity Relationship01:16

Adrenergic Agonists: Chemistry and Structure-Activity Relationship

Adrenergic agonists' structure-activity relationship (SAR) determines their selectivity and efficacy. These agonists comprise a phenylethylamine moiety with an aromatic ring and an ethylamine side chain.
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of the aromatic...
Allosteric Regulation01:08

Allosteric Regulation

Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...
Allosteric Regulation01:08

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Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...
Protein Kinases and Phosphatases02:54

Protein Kinases and Phosphatases

Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
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Amines to Amides: Acylation of Amines01:19

Amines to Amides: Acylation of Amines

Various carboxylic acid derivatives (such as acid chlorides, esters, and anhydrides) can be used for the acylation of amines to yield amides. The reaction requires two equivalents of amines. The first amine molecule functions as a nucleophile and attacks the carbonyl carbon to produce a tetrahedral intermediate. This is followed by the loss of the leaving group and restoration of the C=O bond.
Next, the second equivalent of amine serves as a Brønsted base and deprotonates the quaternary amide...
Phosphorylation01:02

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Related Experiment Video

Updated: Jul 16, 2026

Synthesizing Amino Acids Modified with Reactive Carbonyls in Silico to Assess Structural Effects Using Molecular Dynamics Simulations
05:57

Synthesizing Amino Acids Modified with Reactive Carbonyls in Silico to Assess Structural Effects Using Molecular Dynamics Simulations

Published on: April 26, 2024

Amidine isosteric modification tunes proteolytic stability and activity.

Jacob Byerly-Duke1, Sarah M Bernhard2, Rida Ibrahim1

  • 1Department of Chemistry, Iowa State University Ames IA 50011 USA bvv@iastate.edu.

RSC Chemical Biology
|July 15, 2026
PubMed
Summary

Peptide drugs face rapid breakdown by proteases. Backbone amidine substitution enhances peptide stability and signaling, offering a new strategy for drug development without redesigning the entire peptide.

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LERLIC-MS/MS for In-depth Characterization and Quantification of Glutamine and Asparagine Deamidation in Shotgun Proteomics
08:01

LERLIC-MS/MS for In-depth Characterization and Quantification of Glutamine and Asparagine Deamidation in Shotgun Proteomics

Published on: April 9, 2017

Area of Science:

  • Medicinal Chemistry
  • Peptide Therapeutics
  • Drug Discovery

Background:

  • Peptide therapeutics show great promise but are limited by rapid degradation from proteases.
  • Current stabilization methods often negatively impact peptide conformation and properties.
  • A need exists for effective peptide stabilization strategies that preserve pharmacological profiles.

Purpose of the Study:

  • To investigate backbone amidine substitution as a minimal, site-specific modification for enhancing peptide metabolic stability.
  • To evaluate the impact of amidine substitution on peptide proteolysis and G-protein coupled receptor (GPCR) signaling.
  • To explore the potential of amidines in overcoming limitations of peptide-based drug leads.

Main Methods:

  • Synthesized Leu-enkephalin analogs with backbone amidine substitutions at metabolically labile amide positions.
  • Assessed the susceptibility of amidine-substituted analogs to protease degradation.
  • Evaluated G-protein and β-arrestin signaling pathways for modified analogs at the μ-opioid receptor.

Main Results:

  • Amidine replacement attenuated or blocked proteolysis in a position-dependent manner.
  • One Leu-enkephalin analog with amidine substitution maintained and enhanced G-protein signaling.
  • This analog also demonstrated reduced β-arrestin2 recruitment, suggesting biased agonism.

Conclusions:

  • Backbone amidine substitution is a viable strategy for enhancing peptide metabolic stability.
  • This modification can improve protease resistance without compromising essential pharmacological activity.
  • Amidine substitution offers a modular approach to rescue peptide drug candidates and potentially fine-tune receptor signaling.