With this post, the scientific advisory board of the Boulder Peptide Foundation aims to establish a new tradition: The BPF Journal Club. Monthly, we will feature a reference and commentary on an article within the peptide field that a board member deems significant or interesting for the peptide community. Considering the diverse interests on our board, we believe these articles will be compelling reads.
Today, I'd like to highlight an article that delineates a novel orthogonality in SPPS, DNPBS (https://doi.org/10.1038/s41467-023-41115-x). The authors introduced a new N-alpha protection (DNPBS, 2,4-dinitrobenzenesulfenyl) to peptide chemistry, which is orthogonal to Fmoc, Boc, and potentially Aloc and ivDde/DDe chemistries (although not explicitly tested). Post coupling via classical SPPS methods and activations, DNPBS can be eliminated by p-toluenethiol in pyridine (~12%). While this protective group isn't entirely new—previously used to protect the 5’-OH in oligonucleotide synthesis (for once oligos prove useful)—its application here is innovative.
The authors meticulously prepared the twenty DNPBS N-alpha protected amino acids (employing classical Fmoc side chain protections) and utilized these derivatives to synthesize test peptides via SPPS, achieving considerable success. An intriguing aspect is the absence of detectable racemization during the integration of DNPBS- His(Trt)-OH and DNPBS-Cys(Trt)-OH. Additionally, the deprotection of DNPBS-Asp(OtBu)-OH, while expected, proceeded without aspartimide formation.
It's unlikely that we'll discard all our Fmoc amino acids from the shelf, but it's probable that many will attempt to adapt these reagents for intricate peptide chemistry (think complex multicycle peptides—FOG, are you listening?), even though adequate protection for the corresponding carboxylic groups is yet to be established. Hopefully, someone will replace p-toluenethiol with a less pungent reagent. Although I still feel a nostalgic pang for my younger self—a Post Doc who relished spending late nights in the lab using Reagent K (despite preferring sleep), as the other labs on the floor didn't share my affinity for its scent.
Stay tuned for the February Journal Club article.
Matteo Villain
www.linkedin.com/in/matteo-villain