Ross Cheloha

Last day at #ENDO2025 was great! Amazing symposium on bone and calcium disorders 🦴 by @rche54.bsky.social @MichailLionakis @MichaelMannstadt with great talks on GPCRs and nanobodies, JAK inhibitors in APECED syndrome & new PTH therapies 🤩

Annual Nebraska Drug Discovery and Development Pipeline symposium June 25-26 World-renowned experts will offer their insights during the fifth annual ND3P Symposium, set for June 25-26. The symposium will be virtual and highly interactive.

This Wednesday and Thursday is the VIRTUAL Nebraska Drug Discovery and Development Pipeline Symposium! Registration is still open! Plenary speakers include Brian Kobilka and Virginia Man-Yee Lee.

#chemsky, you should attend!

research.unl.edu/blog/annual-...

Check out the final published product in Journal of Biological Chemistry! www.jbc.org/article/S002...

Excited to see this out in @science.org today!! www.science.org/doi/10.1126/...

Next up, a collaboration with Ross Cheloha's group (@rche54 @rche54.bsky.social) and @MitchellHo leveraging a novel self-labeling approach for site-specific modification of nanobodies for biological applications.

doi.org/10.1002/advs...
3/5

It's been a while since I posted on some of the ☢️ #radiopharmaceuticals ☢️ work we've been brewing.

Let's fix that...

🧵👇
1/5

Great news: NIH postbac program is recruiting again! If your grad school plans were affected by program cutbacks or admissions freezes this year I highly encourage you to apply, this could be a perfect opportunity. Please repost.

www.training.nih.gov/research-tra...

Induced proximity at the cell surface - Nature Biotechnology Technologies to modulate induced proximity at the cell surface advance the manipulation of diverse biological responses.

Check out our new review on induced proximity modalities (#TPD and a lot more!) aimed cell surface targets @naturebiotech.bsky.social, spearheaded by postdocs Nick Till and "Rahm" Ramanathan

www.nature.com/articles/s41...

The findings suggest that optimizing input parameters and refining competition-based modeling approaches may enhance predictive accuracy for antibody-antigen interactions. Intriguing.

🧪 #chembio

Finally we compared models of nanobody-epitope to nanobody-antigen complexes. In one case Alphafold produced an accurate model with epitope but failed with antigen! This highlights the potential utility of simplifying Alphafold inputs for generating models with improved accuracies (4/4)

We further showed that Alphafold could be used in a competition mode to identify peptides that bound nanobody with higher affinity than the wild type epitope peptide. We also used modeling to guide design of a peptide-electrophile conjugate that forms a crosslink with nanobody (3/n)

We performed modeling of experimentally characterized nanobody-peptide interactions and found that 4/6 models matched experimental data. We also crystallized a new nanobody-peptide complex and showed good concordance between the x-ray structure (my first listing on the pdb!) (2/n)

Evaluation of Alphafold modeling for elucidation of nanobody-peptide epitope interactions Models of Ab-antigen complexes can be used to understand interaction mechanisms and to improve affinity. This study evaluates the use of the protein structure prediction algorithm AlphaFold (AF) for e...

Excited to share a preprint covering a collaborative project from my group, the Bewley lab (NIDDK), and the Pierce lab (University of Maryland) describing our first foray into assessing Alphafold for predicting peptide-nanobody interactions (1/n) www.biorxiv.org/content/10.1...

We’re excited to apply this for cell-type specific targeting of gpcrs! Congrats to postdocs Shivani Sachdev and Swarnali Roy on the great work (3/3)

We also show that the activity of these conjugates is dependent on nanobody binding. This property allows us to make conjugates that act in an “and” logic gated manner-only active if 2 different targets are coexpressed on on a single cell. (2/n)

Proud to share this work from my group in the intramural research program at NIH! We describe a new kind of conjugate made from a small molecule adenosine analog linked to a GPCR targeting nanobody to make antibody drug conjugates that potently and specifically activate signaling (1/n) 🧪 #chembio

Nanobody-based conjugates targeting small molecule-binding GPCRs and exhibiting logic-gated signaling https://www.biorxiv.org/content/10.1101/2025.03.07.642093v1

Big gulp 1 gallon drink bag. Big ole plastic bag with a red lid

One good thing I saw today

This work was made possible through contributions from experts in multiple fields (chemistry, cancer imaging, antibody discovery) working together! The methods described may be useful for the development of imaging probes to provide diagnostic info on other types of tumors or other diseases (3/3)

The ability to visualize tumors enables an assessment of whether treatments are working or whether cancer has spread. This imaging requires probes that specifically label cancer cells. We developed a new chemistry for creating probes that label liver cancer tumors. (2/n)

Generation of Site‐Specifically Labeled Affinity Reagents via Use of a Self‐Labeling Single Domain Antibody Several methods have been used to label antibodies to facilitate visualization of cognate targets. Here, we leverage a new variety of conjugation chemistry, based on a crosslinking nanobody, to label...

Proud to share this publication about the development of a new method for visualizing tumors! This work resulted from a close collaboration among 3 groups. (1/n) 🧪@freddyeescorcia.bsky.social
advanced.onlinelibrary.wiley.com/doi/10.1002/...

I'm actually related to him (second cousins or so)! Can definitely ID the 90's Huskers fans by their reaction when I share this connection

Our NCATS research program has a history of collaborating and partnering to get treatments to patients. One of my first goals as SD was to capture and share our success in one place - and here it is!

4 approvals and 56 INDs to date - not bad for 12 years old!

ncats.nih.gov/research/our...

table of contents graphic for review titled synthetic lipid biology

abstract of review article

Po-Hsun Brian Chen

Xiang-Ling (Julia) Li

Overjoyed and honestly relieved to share a Chem Rev magnum opus from Brian Chen & Julia Li titled Synthetic Lipid Biology! In it, we organize efforts across numerous fields to create, manipulate, and analyze lipids and biomembranes. Check it out! doi.org/10.1021/acs.... #lipidtime #chemsky #chembio

Development of mirror-image monobodies targeting the oncogenic BCR::ABL1 kinase - Nature Communications In this work, the authors develop mirror-image monobodies (Mb) made of D-amino acids against the BCR::ABL1 SH2 domain with high binding affinities. The heterochiral Mb-SH2 structures reveal an unusual...

🎄Xmas gift!🎁Joint work with #OliverHantschel in @naturecomms.bsky.social 💥! Huge kudos 💪🏼😻 Nina 👩‍🔬 for leading as 1st author & Frank 👨🏼‍🔬 for training her like a pro❤️
Small delay😅 -my👵broke her hip🤦🏼‍♀️-loved ones always come first❤️surgery went good💪🏼🤩Let's celebrate🥳🥂! #ChemBio
www.nature.com/articles/s41...

1/ In two back-to-back papers, we present our de novo TRACeR platform for targeting MHC-I and MHC-II antigens

TRACeR for MHC-I: go.nature.com/4gcLzn5
TRACeR for MHC-II: go.nature.com/4gj5OQk

Retention of Native Quaternary Structure in Racemic Melittin Crystals Racemic crystallography has been used to elucidate the secondary and tertiary structures of peptides and small proteins that are recalcitrant to conventional crystallization. It is unclear, however, w...

I think antimicrobial peptides would even work fine (don't act via a membrane receptor): pubs.acs.org/doi/10.1021/...

Mostly, the immune system would lose nucleic acid sensing TLR responses and the T cell branch of adaptive immunity (and perhaps B cell/antibody maturation from T cell co-stim)

Confronting risks of mirror life Broad discussion is needed to chart a path forward.

A thought provoking scenario: what would happen if "mirror" (reverse chirality) microbe were created and released? The time estimate (10 years) seems long to me as there's been incredible progress in making mirror enzymes. You don't need much of a few mirror enzymes for a self sustaining cascade..🧪

Congrats @djenetbousbaine.bsky.social and all the authors--awesome work!