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Macrocyclic Peptides as Allosteric Inhibitors of Nicotinamide N-Methyltransferase (NNMT)

submitted on 18.09.2020 and posted on 18.09.2020 by Matthijs J. van Haren, Yurui Zhang, Ned Buijs, Vito Thijssen, Davide Sartini, Monica Emanuelli, Seino Jongkees, Nathaniel Martin

Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide to form 1-methylnicotinamide using S-adenosyl-l-methionine (SAM) as the methyl donor. The complexity of the role of NNMT in healthy and disease states is slowly being elucidated and provides indication that NNMT may be an interesting therapeutic target for a variety of diseases including cancer, diabetes, and obesity. Most inhibitors of NNMT described to date are structurally related to one or both of its substrates. In search of structurally diverse NNMT inhibitors, an mRNA display screening technique was used to identify macrocyclic peptides which bind to NNMT. Several of the cyclic peptides identified in this manner show potent inhibition of NNMT with IC50 values as low as 229 nM. Interestingly, substrate competition experiments reveal that these cyclic peptide inhibitors are noncompetitive with either SAM or NA indicating they may be the first allosteric inhibitors reported for NNMT.


Email Address of Submitting Author


Institute of Biology Leiden, Leiden University



ORCID For Submitting Author


Declaration of Conflict of Interest

The authors declare no conflicts.


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