Insight

Proteomic Barcoding Platform for Macromolecular Screening and Delivery

Photo of Alex Kentsis from X

Jul 3, 2024, 21:42

Proteomic Barcoding Platform for Macromolecular Screening and Delivery

Alex Kentsis, Director of the Tow Center for Developmental Oncology, shared on LinkedIn:

“Interested in drug delivery and screening? Read our latest by Ning Wang et al, Proteomic Barcoding Platform for Macromolecular Screening and Delivery.

Peptide barcoding combined with high-resolution mass spectrometry was recently introduced as a powerful tool for both small molecule and macromolecular drug screening.

While readily accessible on current high-resolution mass spectrometers, the design of accurate peptide barcode libraries remains largely ad hoc.

Similarly, recent advances in macromolecular screening have identified various cell penetrating peptides for cellular delivery, but their use is hindered by their relatively low efficiency and cytotoxicity.

In this new paper, we now describe two new open-source tools, BarcodeBabel, a generalized method for the design of arbitrarily large libraries of unique peptide barcodes suitable for high-throughput mass spectrometry proteomics, and PeptideBabel, a Monte Carlo sampling algorithm for the design of peptides with evolvable physicochemical properties and sequence complexity.

We apply these tools in a proof-of-concept study to design novel barcoded cell penetrating peptides, and investigate them using high-resolution targeted quantitative mass spectrometry to identify novel cell penetrating peptides with improved nuclear and cytoplasmic delivery, while maintaining minimal membrane disruption and negligible toxicity in human cells in vitro.

These studies provide proof-of-concept for peptide barcoding as a homogeneous high-throughput method for macromolecular screening and delivery.

BarcodeBabel and PeptideBabel enable the construction of barcoded libraries of peptidic macromolecules with varied biological activities, and thus should be useful for a wide variety of molecular evolution and screening applications.

For example, this approach may be used to design novel protein binders and quantify their binding affinities and kinetics using libraries of purified barcoded proteins in vitro.

Given the high sensitivity and resolving power of modern mass spectrometers, similar screens may also be performed with libraries of barcoded macromolecules injected intravenously, and quantified using proteomics of specific tissues and organs in vivo.

We expect that the open and scalable framework of BarcodeBabel and PeptideBabel established by this work will lead to the development of improved tools for peptide and protein design using mass spectrometry proteomics.

The use and further development of novel cell penetrating peptides identified in this work should lead to improved methods for macromolecular drug delivery, which is one of the major barriers in modern pharmacology.”

Read further.
Source: Alex Kentsis/LinkedIn