The Drew Weissman Lab

@drewweissmanlab.bsky.social

Bringing mRNA therapeutics to the world. University of Pennsylvania https://www.med.upenn.edu/weissmanlab/

Harnessing the Electron-Withdrawing Inductive Effect of One-Component Ionizable Amphiphilic Janus Dendrimers Unveils Cation−π Interactions and Their Important Roles to Targeted mRNA Delivery | Journal of the American Chemical Society pubs.acs.org/doi/10.1021/...

Harnessing the Electron-Withdrawing Inductive Effect of One-Component Ionizable Amphiphilic Janus Dendrimers Unveils Cation−π Interactions and Their Important Roles to Targeted mRNA Delivery

It is expected that current medicine will be complemented or even replaced with genetic nanomedicine, which relies on the targeted delivery of nucleic acids. Delivery of mRNA is accomplished using viral and synthetic four-component vectors which deliver the nucleic acid predominantly to the liver. Our laboratories elaborated a one-component ionizable amphiphilic Janus dendrimer (IAJD) which targets the delivery of mRNA and, therefore, is complementary to viral and synthetic vectors. Here we report the study of a library of IAJDs containing derivatives of the natural gallic acid (GA) as branched hydrophobic domain and two ionizable amines connected via four linker length. The linker length mediates an electron-withdrawing inductive effect, which changes the pKa of the IAJDs. The same pKa trend was observed in a previously reported pentaerythritol (PE)-library, which has structures identical to those of the GA-library except that it does not contain the aromatic ring. Unpredictable, the GA-library of IAJDs has consistently higher pKa values than the PE-library, although the linker length-pKa dependence follows the same trend in both libraries. This trend indicates an unexpected cation−π interaction which explains some advantages of GA-IAJDs, including the 109 p/s total luciferase activity reported here.

pubs.acs.org

Several months ago, I was honored to be invited by JMB Editor-in-Chief Mike Summers to write a Perspective for the Pioneers in Molecular Biology special issue. It was a chance to reflect on the journey that led me here. You can read the pieces here: tinyurl.com/2pb967u9 & tinyurl.com/kkwfynt2

Making Every Penny Count: Kinase Signaling Transduction, Copper Homeostasis, & Nutrient Sensing

I am the Harrison McCrea Dickson, MD, and Clifford C. Baker, MD Presidential Associate Professor of Cancer Biology at the University of Pennsylvania P…

tinyurl.com