Spotlight on: Cyclic peptides

What are cyclic peptides?

Cyclic peptides are a diverse group of bioactive compounds that are present in almost all living organisms, from plants, bacteria, and animals. They are a distinct category of peptide compounds in which the peptide chain forms a continuous loop via covalent bonds, differentiating them from their linear peptide siblings.

Their great diversity means their therapeutic uses are wide-ranging: from antibiotics, antifungals, antiparasitics, and immune modulators to anti-inflammatory agents. In pharmaceutical therapies, cyclic peptides are an exciting and increasingly important class of molecules, offering a unique blend of properties that bridge the gap between small molecules and biologics. Because of their shape, they exhibit conformational stability and protection against enzymatic breakdown, giving them a unique ability to serve distinctive biological functions compared to linear peptides.

Why are cyclic peptides both challenging and interesting?

Cyclic peptides pose several analytical challenges in drug development and characterization due to their multiple conformations. Additionally, their many intramolecular interactions, hydrogen bonding, and steric effects can obscure functional groups, complicating spectroscopic analyses such as NMR.

While LC-MS analysis can be complex, it offers the benefit of separating cyclic peptides from impurities, degradation products, and uncyclized precursors. When performing bioanalysis experiments, this is especially useful for analyzing synthetic mixtures or biological samples such as plasma or tissue extracts. Sensitive mass spectrometric detection enables the detection of low-level analytes and distinguishes between closely related analogs, including isomers and modified peptides.

How are cyclic peptides impacting the world?

Cyclic peptides are unlocking undruggable targets. Many diseases are driven by protein-protein interactions, which are notoriously difficult to target with traditional small molecules. Cyclic peptides can bind tightly and selectively to these interfaces, making them ideal for modulating protein-protein interactions. Some examples of where they are currently being used include organ transplantation (kidney, liver, and heart) to prevent rejection, autoimmune diseases such as rheumatoid arthritis, and in the treatment of psoriasis.

There are over 40 cyclic peptides currently approved and used as clinical therapeutics, many of which are natural peptides. In the last few decades, an emerging trend in drug discovery has been the optimization of naturally isolated cyclic peptides to improve aspects like stability, potency, and pharmacokinetic properties via chemical synthesis, computational, and in vitro methods – allowing for a great variety of drug delivery methods.

How does SCIEX help overcome key challenges?

Along with the emerging interest in advancing cyclic peptide therapeutics, there is a corresponding drive to develop highly robust and sensitive quantitative methods. Current bioanalytical methods lack the sensitivity necessary to reliably quantify cyclic peptides. For LC-MS-based methods, high baseline interference in single MS mode and resistance to CID in MS/MS mode, due to the tertiary structure, affect overall sensitivity.

The SCIEX 7500+ system is a great option for cyclic peptide analysis because it offers exceptional sensitivity for low-level analytes and continuous robust performance, even in complex matrices. And when high resolution is needed to separate closely eluting analytes with similar masses or background noise, the SCIEX 7600+ system is an excellent choice. Both systems are powered by SCIEX OS software, which is streamlined for data acquisition, processing, and management – all in a 21 CFR Part 11 compliance-ready environment.

Key benefits of cyclic peptides

Legumes produce cyclic peptides to defend against pathogens, whereas marine animals, like sponges and cone snails, produce peptides that act as toxins for predation or defense
Many cyclic peptides produced by bacteria (like subtilin from Bacillus subtilis) are also used as a defense mechanism to inhibit other microorganisms
Meanwhile, fungal cyclic peptides are a key source for peptides with immunomodulatory properties
Outside of drug molecules, cyclic peptides are used in biosensor development – like, tumor marker detection for early cancer diagnosis
They are also used in materials science for tissue engineering, or they can be used to encapsulate other drug molecules enabling controlled release and efficacy

Explore more below:

Low-pg/mL quantification of cyclic peptides in rat plasma using microflow LC

This technical note describes the enhancement of lower limits of quantification (LLOQs) for cyclic peptides by using a microflow trap-and-elute method.

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Improved LC-MRM Sensitivity for Cyclic Peptide Quantification on Natriuretic Peptide Family

See how outstanding reproducibility, accuracy, and linearity was achieved, proving the workflow robustness in parallel with the superior sensitivity.

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Sensitive LC-MRM HR approach for cyclic peptide quantitation inhuman plasma

See how a lower limit of quantitation (LLOQ) of 0.05 ng/mL was achieved in extracted plasma samples.

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A simple and highly sensitive solution for the quantification of cyclic peptides

Low-level quantification was achieved with outstanding accuracy, precision and linearity.

Solution

Ultimate quantitation

Benefits:

Reliably quantify at low limits
Future-proof your methods

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ExionLC AE system

Reproducibility, reliability and carryover performance to match your quantitative workflows. Dependability you can count on, from injection to injection and batch after batch.

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