A new collaborative paper on unnatural N-acyl amino acids

Our new collaborative paper between four (!) laboratories is out today in J. Med. Chem. With help from the Nomura, Spiegelman, Griffin, and Kamanecka groups, we have performed a comprehensive structure-activity relationship study of the N-acyl amino acids and their chemical uncoupling bioactivity. You can read more about it here.

I wanted to use this opportunity to describe the context of this work in a little more detail. Chemical uncoupling is a powerful and proven strategy for increasing energy expenditure and reducing weight in humans. Discovered nearly 100 years ago, chemical uncouplers like 2,4-dinitrophenol (DNP) are still used off label today as "diet pills." Of course, their narrow therapeutic index (which can lead to overheating and death) severely limits their general utility for weight loss.

Recently, there has been renewed interest in other structural scaffolds that might be useful for chemical uncoupling. For instance, there are reports of DNP derivatives with potentially wider therapeutic ratios or structurally distinct "mild" chemical uncouplers. Our own work relates to a class of endogenous metabolites, the N-acyl amino acids. In our original report, we discovered that N-acyl amino acids can act as endogenous chemical uncouplers. Furthermore, the previously unknown circulating enzyme PM20D1 is a key enzymatic regulator of this lipid class.

We were curious about whether N-acyl amino acids might be diversifiable by chemical synthesis to produce new analogs with potentially improved properties. In this JMC paper we describe these synthetic efforts. In fact, we stumbled upon a class of unnatural, isoindoline containing N-acyl amino acids that exhibit improved uncoupling bioactivity and resistance to degradation. Importantly, these isoindoline derivatives are also bioactive uncouplers in diet-induced obese (DIO) mouse models. Ultimately more work will be needed to determine whether these compounds are significantly "better" (e.g., safer or more potent) in vivo than the natural N-acyl amino acids. Nevertheless, the main takeaway is that diversification of N-acyl amino acid structures can yield improved uncouplers that might also serve as useful tool compounds for N-acyl amino acid biology.

This work represents some of the last few things I was doing during my time with Bruce at DFCI/HMS prior to transitioning to Stanford. We have another manuscript in the works on the biology of N-acyl amino acids. Check back soon for more updates! -JZL