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Alexander L. Nielsen @alexanderln.bsky.social · Jun 10

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

Nathalie M. Grob @nathalie-grob.bsky.social · Jun 10

We are hiring! Check out our open PhD position for an exciting industry collaboration with Novo Nordisk:
jobs.ethz.ch/job/view/JOP...

PhD Position in Peptide-Based Drug Discovery (Industry Collaboration, w/m/d)

jobs.ethz.ch

Alexander L. Nielsen @alexanderln.bsky.social · Jun 2

Thank you for the kind words, Joshua!

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Alexander L. Nielsen @alexanderln.bsky.social · Jun 2

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.

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Alexander L. Nielsen @alexanderln.bsky.social · Jun 2

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/🧵)

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Alexander L. Nielsen @alexanderln.bsky.social · Jun 2

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/🧵)

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Alexander L. Nielsen @alexanderln.bsky.social · Jun 2

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/🧵)

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Alexander L. Nielsen @alexanderln.bsky.social · Jun 2

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/🧵)

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Alexander L. Nielsen @alexanderln.bsky.social · Jun 2

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/🧵)

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Alexander L. Nielsen @alexanderln.bsky.social · Jun 2

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/🧵)

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Alexander L. Nielsen @alexanderln.bsky.social · Jun 2

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/🧵)

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Alexander L. Nielsen @alexanderln.bsky.social · Jun 2

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/🧵)

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Alexander L. Nielsen @alexanderln.bsky.social · Jun 2

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/...

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 ...

onlinelibrary.wiley.com

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Alexander L. Nielsen @alexanderln.bsky.social · May 8

Exciting opportunity to join our US research site!
#chemjobs

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

Senior Scientist I - Peptide and Macrocycle Chemistry

careers.novonordisk.com

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Alexander L. Nielsen @alexanderln.bsky.social · Mar 24

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/

Post-Doctoral Research Associate (Fixed Term) - Job Opportunities - University of Cambridge

Post-Doctoral Research Associate (Fixed Term) in the Yusuf Hamied Department of Chemistry at the University of Cambridge.

www.jobs.cam.ac.uk

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Alexander L. Nielsen @alexanderln.bsky.social · Feb 19

Thanks for the (long) ride! 😎

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Reposted by Alexander L. Nielsen

Carlos Moreno-Yruela @carlosmyruela.bsky.social · Feb 19

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

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 ...

pubs.acs.org

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Alexander L. Nielsen @alexanderln.bsky.social · Feb 16

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

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Reposted by Alexander L. Nielsen

Carlos Moreno-Yruela @carlosmyruela.bsky.social · Feb 4

#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

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Alexander L. Nielsen @alexanderln.bsky.social · Jan 13

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

Craig Day @craigday.bsky.social · Jan 13

𝐏𝐡𝐃 𝐏𝐨𝐬𝐢𝐭𝐢𝐨𝐧𝐬 𝐚𝐯𝐚𝐢𝐥𝐚𝐛𝐥𝐞! 🎉

The Day lab is hiring two PhD candidates to work on developing new transition-metal-catalyzed methods to transform CO2 into polymers or pharmaceuticals!

jobportal.ku.dk/phd?show=163...

Applications are open until February 14th 2025.

Please feel free to share!

PhD fellowship in synthesizing CO2-derived materials

jobportal.ku.dk

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Reposted by Alexander L. Nielsen

Karl Gademann @karlgademann.bsky.social · Jan 9

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

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...

jobs.uzh.ch

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Reposted by Alexander L. Nielsen

Daniela Danková @danieladankova.bsky.social · Dec 13

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).

Christian A. Olsen @christianaolsen.bsky.social · Dec 10

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...

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Reposted by Alexander L. Nielsen

Christian A. Olsen @christianaolsen.bsky.social · Dec 10

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...

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Alexander L. Nielsen @alexanderln.bsky.social · Dec 9

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...

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 ...

chemrxiv.org

4 7

Alexander L. Nielsen @alexanderln.bsky.social · Nov 30

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

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 ...

www.nature.com

3

Alexander L. Nielsen @alexanderln.bsky.social · Jan 15

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/...