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Macrocyclic peptide screening

Angewandte Chemie International Edition (2020). DOI: 10.1002 / anie.202013392 “width =” 732 “height =” 168 “/>

Credit: Ganga B. Vamisetti et al, Development of a fluorescence-based competitive assay has enabled the discovery of a dimeric cyclic peptide modulator of the ubiquitin chain. Angewandte Chemie International Edition (2020). DOI: 10.1002 / anie.202013392

Macrocyclic peptides are promising drug candidates, but their screening is difficult. Scientists have now developed an easy-to-use high-throughput screening assay for cyclic peptides that have an affinity for ubiquitin, a protein that aids in proteolysis and induction of cell death.Results may lead to new drug candidates for cancer, according to studies published in the journal Angewandte Chemie..


Drugs based on peptides (small proteins) are often too large to cross cell membranes. To make such peptides more compact, stable, and therefore more efficient, researchers are investigating a closed version called the macrocyclic peptide. Drugs based on macrocyclic peptides are interesting candidates for the regulation of regulatory proteins, an important goal in cancer research.

However, screening for such peptides is difficult. “Established screening approaches often require very expensive equipment and proper training,” says Israel Technion-Israel Institute of Technology Ashram Brig, which was established to develop alternative strategies.

Researchers have designed a simple screening assay based on competitive binding. Competitive binding means that an unknown peptide is tested for its ability to replace a known peptide with a known binding affinity for a target. The readout is simply a change in fluorescence and is provided by a fluorescent label attached to a known peptide. Researchers say this setting allows for fast, high-throughput, inexpensive, and easy-to-implement screening of peptide libraries.

Researchers used this assay to screen for peptides that bind strongly to ubiquitin, a small cellular protein that cells use to tag dysfunctional proteins and mark them for degradation. They identified several peptide candidates with high binding affinities. You can further tune these candidates to make them more functional.

“For example, we exposed peptides to chemical reactions such as alkylation arylation, oxidation, and dimerization, which is the first step in making polycyclic peptides,” says Brik. “Polycyclic peptides have important added value to be considered drug candidates.” Scientists say that cyclization makes peptides more stable than open analogs, and their compact shape makes them easier to enter cells. I think it will be.

The authors prepared a dimer of a cyclic ubiquitin-binding peptide to which two identical cyclic peptides were bound and rescreened for ubiquitin affinity. They found candidates for strong binding and tested them for their regulatory role in living cancer cell lines. The authors found that dimeric cyclic peptides easily invade cells and induce cell death, which are more potent than control peptides.

In addition, the authors suggest that the novel cyclic peptide can be labeled and used as a stain for ubiquitin with antibody-like properties.


Oliguria foldamers mimic the peptide alpha helix and effectively bind to drug targets


For more information:
Ganga B. Vamisetti et al, developing a fluorescence-based competitive assay, has enabled the discovery of a dimeric cyclic peptide modulator of the ubiquitin chain. Angewandte Chemie International Edition (2020). DOI: 10.1002 / anie.202013392

Quote: Https: //phys.org/news/2021-02-screening-macrocyclic-peptides.html Screening for macrocyclic peptides obtained on February 22, 2021 (February 22, 2021)

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