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Discover the Future of Vaccination: Introducing 'String-of-Beads' Vaccines. In this enlightening Nature Communications article, Dasari et al. unveil the revolutionary development of an Epstein-Barr virus (EBV) vaccine, employing a cutting-edge multi-epitope subunit approach (https://doi.org/10.1038/s41467-023-39770-1). This breakthrough paves the way for analogous advancements in infectious and cancer vaccine research, driven by substantial enhancements in the biochemical production of such sophisticated constructs. Mirroring the principles of mRNA vaccine strategies, these novel approaches promise superior performance through improved stability and enhanced delivery to MHC complexes, all while eliminating the reliance on mRNA-based biosynthesis within human cells. Check out how these innovations could redefine disease prevention and treatment.

Christian Schwarz, Ph.D.
Member, BPF Scientific Advisory Board
https://www.linkedin.com/in/christian-dr-schwarz-8a314b155

The February BPS Journal Club explores lasso peptides, a fascinating class of bioactive macrocyclic peptide natural products. These peptides have a unique structure with a threaded (rotaxane) motif, where the C-terminal tail is captured within a macrolactam through an isopeptide bond. The lasso fold provides pharmacokinetic advantages, including high proteolytic and metabolic stability, along with resistance to degradation. This defined structure can be utilized to optimize interactions with therapeutically relevant targets.

Chemical synthesis of lasso peptides poses a significant challenge, as the nonthreaded isomer (referred to as a tadpole isomer) is kinetically favored over forming the lariat knot-like fold. While companies like Lassogen are making significant progress with engineered therapeutic lasso peptides (Lassotides™), reliance on biosynthetic routes limits the incorporation of noncanonical amino acids and other structural investigations.

A team led by Professor Andrew G. Roberts at the University of Utah recently reported the solid-phase peptide synthesis of cyclic, cyclic-branched (tadpole), and linear isomers of sungsanpin and ulleungdin, lasso peptide natural products known to inhibit cell migration in models of metastasis (https://pubs.acs.org/doi/10.1021/acschembio.3c00525¹).  Prof. Roberts and collaborators discovered that the lasso motif itself was not critical for inhibition of cell migration by synthetically accessible analogs of these natural products.

In their publication, the Roberts group details a general approach to the SPPS and on-resin cyclization of lasso peptide isomers and highlights the use of Fmoc-Asp(CSY)−OH (CAS 2379679-90-8) to mask the carboxylic acid functionality of Asp in certain aspartimide prone sequences. So, while the class II lasso scaffold remains a synthetic challenge yet to be overcome, the Roberts group and collaborators remind us that promising hits can be obtained from evaluating structurally complex natural molecules and applying ingenuity in peptide design to discover chemically tractable leads.

1. Nonthreaded Isomers of Sungsanpin and Ulleungdin Lasso Peptides Inhibit H1299 Cancer Cell Migration; Lori Digal, Shiela C. Samson, Mark A. Stevens, Abhijit Ghorai, Hyungyu Kim, Marcus C. Mifflin, Keith R. Carney, David L. Williamson, Soohyun Um, Gabe Nagy, Dong-Chan Oh, Michelle C. Mendoza, and Andrew G. Roberts. ACS Chemical Biology 2024 19 (1), 81-88. DOI: 10.1021/acschembio.3c00525

Wendy Hartsock
Member, BPF Scientific Advisory Board
https://www.linkedin.com/in/wendy-hartsock-49938512/

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