Alexander L. Nielsen

Looking for a PhD in peptide chemistry?
Apply for this exciting collaboration between Novo Nordisk and the Grob lab at ETH!

Thank you for the kind words, Joshua!

To finish off.
Thanks to all collaborators on this work!
I had the most amazing postdoc surrounded by talented co-workers and collaborators. It would not have been possible without you. (10/🧵-end)

Also, I hope you enjoy the work and can apply the model and/or the CAPA amino acids in future work.

Hopefully the model can/will be re-fitted with additional permeability data from even larger/complex libraries in the future. However, this was how it ended with me leaving academia (albeit staying in research, now in industry at Novo🐂👨‍🔬). (9/🧵)

Finally, we teamed up with @pschwllr.bsky.social @rebeccaneeser.bsky.social who prepared a random forest model that can readily applied to estimate the membrane permeability of designed cyclic peptides.
Model available on GitHub: github.com/schwallergro...
(8/🧵)

This gave us deep insight into the permeability of an unprecedented number of compounds in CAPA.
We also recapitulated that exceeding a MW of 800 Da, a PSA of 250 Å2, or 5 HBDs had a small chance of having a good membrane permeability - although there can be outliers. (7/🧵)

After some synthesis iterations, we designed a diverse random library of 192 CA-peptides. Despite some issues with diketopiperazine (DKP) by-products, we obtained 143 macrocycles for subsequent crude analysis in CAPA. (6/🧵)

We next developed a crude synthesize strategy to synthesize crude CA-tagged macrocycles (based on previous workflow: onlinelibrary.wiley.com/doi/10.1002/...), and we saw that crude peptides tested in CAPA gave rise to similar half-maximal cell penetration (CP50) values to purified compounds. (5/🧵)

To make CAPA directly compatible with automated SPPS, I synthesized new (and less polar) CA-tagged amino acids that allowed for easy and direct incorporation into macrocycles. We showed that permeability was nicely retained in known model peptides such as CsA bearing the new amino acid(s). (4/🧵)

One of the caveats with CAPA for passively permeable compounds is the relatively large (commercial) succinyl-chloroalkane tag (Suc-CA).
Permeability was negatively impacted >10-fold compared to installing a smaller CA-tag onto macrocycle scaffolds with known good passive permeability. (3/🧵)

This work was conceptualized by me and my good friend and co-first author Dr. Christian Bech-Bartling at @ucph.bsky.social. We merged our shared interests for macrocycles, high-throughput and the chloroalkane penetration assay (CAPA, first developed by @chemkritzer.bsky.social) and got started (2/🧵)

Bulk Measurement of Membrane Permeability for Random Cyclic Peptides in Living Cells to Guide Drug Development Some cyclic peptides can cross membranes, which is highly attractive for drug development, but it remains difficult to accurately predict membrane permeability or to test it experimentally for large ...

Very pleased to share the 'last' first-author paper from my postdoc with Prof. Christian Heinis at EPFL.
Now out in its final form in @angewandtechemie.bsky.social as a 'Very Important Paper' 🔥 (1/🧵) #chemsky
onlinelibrary.wiley.com/doi/10.1002/...

Exciting opportunity to join our US research site!
#chemjobs

careers.novonordisk.com/job/Lexingto...

Sharing for better reach:

Join a fun, talented and social lab.
#postdocjob available in the Knowles group
(Univ. of Cambridge).
Experience with mRNA/phage/yeast display is a plus.
www.jobs.cam.ac.uk/job/50546/

Thanks for the (long) ride! 😎

Discovery of De Novo Macrocycle Inhibitors of Histone Deacetylase 11 Histone deacetylase (HDAC) enzymes are epigenetic regulators that affect diverse protein function by removing acyl groups from lysine side chains throughout the proteome. The most recently discovered ...

Very happy to see this story out in #JACS_Au!

Discovery of De Novo Macrocycle Inhibitors of Histone Deacetylase 11
pubs.acs.org/doi/10.1021/...

#ChemBio #chemsky #HDAC

Our work on macrocyclic HDAC11 inhibitors is now out in JACS Au! pubs.acs.org/doi/10.1021/...
#openaccess #chemsky

#SIRT7 is a histone deacetylase with highly specific activity on #chromatin substrates.
We just published mechanism-based #cryoEM structures of #SIRT7 on nucleosomes to understand its activity 👇
www.nature.com/articles/s41...
(1/8) #ChemBio #ChemSky

Come join Craig in his new lab in wonderful Copenhagen! 🇩🇰

UZH: PhD Student Position in Peptide Chemistry A PhD Student position is available in the group of Prof. Dr. Karl Gademann, located in the Department of Chemistry at the University of Zurich (Switzerland). Our group combines the synthesis of natur...

We are hiring! Exciting project on the performance enhancement of peptides. Check out and share: jobs.uzh.ch/job-vacancie...

Happy to share the latest preprint from my PhD studies on the discovery of de novo macrocyclic inhibitors of HDAC11. This was a great collaboration between @christianaolsen.bsky.social lab (@carlosmyruela.bsky.social, @tnhansen.bsky.social) and Christian Heinis lab (@alexanderln.bsky.social).

New preprint @chemrxiv.bsky.social on discovery of macrocyclic inhibitors of HDAC11 with the Christian Heinis #EPFL

Main contributors @danieladankova.bsky.social, @alexanderln.bsky.social, @carlosmyruela.bsky.social

🙏 @ERC_Research, @novonordiskfond, @DFF_raad for 💶

chemrxiv.org/engage/chemr...

Discovery of de novo Macrocycle Inhibitors of Histone Deacetylase 11 Histone deacetylase (HDAC) enzymes are epigenetic regulators that affect diverse protein function by removing acyl groups from lysine side chains throughout the proteome. The most recently discovered ...

Happy to share a fun collaboration between EPFL and UCPH initiated by @carlosmyruela.bsky.social, Christian Heinis, @christianaolsen.bsky.social and I!

Big shout-out to @danieladankova.bsky.social who spearheaded the project.

Now out on @chemrxiv.bsky.social

chemrxiv.org/engage/chemr...

Photochemically-enabled, post-translational production of C-terminal amides - Nature Communications C-terminal α-amidated peptides are attractive therapeutic targets, but preparative methods to access amidated pharmaceuticals are limited both on lab and manufacturing-scale. Here, the authors report ...

Amazing work by my colleagues! Now out in Nature Comms!
www.nature.com/articles/s41...

Latest paper from the Heinis lab. Solid-phase peptide synthesis in 4 × 384 well-plates to prepare 1,536 peptides per run! Out now in J. Pept. Sci!
onlinelibrary.wiley.com/doi/10.1002/...

De novo development of small cyclic peptides that are orally bioavailable - Nature Chemical Biology Cyclic peptides show promise for modulating difficult disease targets; however, they often cannot be administered orally. The authors developed a method to synthesize and screen large libraries of sma...

The latest paper from the Heinis on the development of orally available cyclic peptides is finally out in Nature Chemical Biology! Big congrats to Manuel who spearheaded this project!
www.nature.com/articles/s41...