ADVERTISEMENT
2 /3 FREE ARTICLES LEFT THIS MONTH Remaining
Chemistry matters. Join us to get the news you need.

If you have an ACS member number, please enter it here so we can link this account to your membership. (optional)

ACS values your privacy. By submitting your information, you are gaining access to C&EN and subscribing to our weekly newsletter. We use the information you provide to make your reading experience better, and we will never sell your data to third party members.

ENJOY UNLIMITED ACCES TO C&EN

Pharmaceuticals

Replacing inhibitor’s hydrogen bond boosts potency


Peptide blocks key signaling pathway involved in cancer and other diseases

by Celia Henry Arnaud
November 3, 2016 | APPEARED IN VOLUME 94, ISSUE 44

In a new NF-κ inhibitor (right), a hydrogen bond between an aspartic acid and a serine in the original peptide (left) is replaced by a covalent bond between two allylglycines (center). In each structure, W739 is a tryptophan.

Replacing a hydrogen bond with a covalent bond boosts the potency of a peptide inhibitor of a key cellular signaling pathway implicated in cancer and other diseases.

The signaling protein central to this pathway is NF-κB. One way to block NF-κB signaling is by disrupting protein-protein interactions in a complex that regulates NF-κB activation. An inhibitor of this complex called the NEMO binding domain (NBD) peptide was reported more than a decade ago. But that inhibitor wasn’t very stable and so it became a therapeutic dead end.

Anna K. Mapp and coworkers at the University of Michigan have come up with a modification that stabilizes the inhibitor and boosts its potency significantly in cell assays (Angew. Chem. Int. Ed. 2016, DOI: 10.1002/anie.201607990).

A hydrogen bond is critical for stabilizing the original inhibitor when it binds to NEMO, a protein in the NF-κB-regulating complex. The amino acids that form the hydrogen bond aren’t involved in other interactions.

That led Mapp’s grad student Paul A. Bruno to hypothesize that they “could replace that hydrogen bond with something more stable, hopefully without losing a lot of binding affinity,” she says. They replaced the participating aspartic acid and serine with two allylglycines, which they then connected via olefin metathesis. The changes may have slightly reduced the binding affinity, Mapp says, but the improved stability against protein-degrading enzymes more than compensates.

“Despite high interest and widespread use of the NBD peptide in both cellular and animal models exploring NF-κB activation, this is notably the first instance of a molecule with improved efficacy since the original report of the NBD peptide in 2000,” says Maria Pellegrini, a chemist at Dartmouth College, who studies protein-protein interactions. “Molecules with improved affinity and metabolic stability are a welcome addition to the arsenal of tools for the study of NF-κB signaling and open the way for the development of peptide-based therapeutics.”

X

Article:

This article has been sent to the following recipient:

Comments
Bakhtiar Khodavirdilo (November 9, 2016 1:56 PM)
I was worked in phd field about removal of heavy metal ions from aqueous solutions using various adsorbents

Leave A Comment

*Required to comment