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[159.112.244.34]) by mx.google.com with UTF8SMTPS id 6a1803df08f44-8b53da24de5si92936716d6.602.2026.05.03.07.41.34 for (version=TLS1_2 cipher=ECDHE-ECDSA-AES128-GCM-SHA256 bits=128/128); Sun, 03 May 2026 07:41:34 -0700 (PDT) Received-SPF: pass (google.com: domain of bounce+91e48a.63af5d-tjphuhs=gmail.com@mg-d0.substack.com designates 159.112.244.34 as permitted sender) client-ip=159.112.244.34; Authentication-Results: mx.google.com; dkim=pass header.i=@mg-d0.substack.com header.s=mailo header.b=fOIVh5lo; dkim=pass header.i=@mailgun.org header.s=mg header.b=sUF6JAlg; spf=pass (google.com: domain of bounce+91e48a.63af5d-tjphuhs=gmail.com@mg-d0.substack.com designates 159.112.244.34 as permitted sender) smtp.mailfrom="bounce+91e48a.63af5d-tjphuhs=gmail.com@mg-d0.substack.com"; dmarc=pass (p=REJECT sp=REJECT dis=NONE) header.from=substack.com DKIM-Signature: a=rsa-sha256; v=1; c=relaxed/relaxed; d=mg-d0.substack.com; q=dns/txt; s=mailo; t=1777819294; x=1777826494; h=List-Unsubscribe-Post: List-Unsubscribe: List-Post: List-Id: List-Archive: List-Owner: Reply-To: In-Reply-To: References: Sender: Sender: Date: Message-Id: To: To: From: From: Subject: Subject: Content-Type: Mime-Version: X-Feedback-Id; bh=UtbiQPX4EGNg//c752bUmnMD0tnaNGTaEOdEANg73Eo=; b=fOIVh5lojFixBV6IDaGle1GbMSEA7vTwiUgfTvFoDdUvTrQkXVyqpbErplrdf7gUS3xy4aWXU6yQZUFdg4oP6M69ILnvE5s+3oF0WsVc9sxw46961tc1rt3fM+CW9vhx/utHuS+MNcJ8jjKJvncNLUGA8SnDkiHWI4BF/0s9ups= DKIM-Signature: a=rsa-sha256; v=1; c=relaxed/relaxed; d=mailgun.org; q=dns/txt; s=mg; t=1777819294; x=1777826494; h=List-Unsubscribe-Post: List-Unsubscribe: List-Post: List-Id: List-Archive: List-Owner: Reply-To: In-Reply-To: References: Sender: Sender: Date: Message-Id: To: To: From: From: Subject: Subject: Content-Type: Mime-Version: X-Feedback-Id; bh=UtbiQPX4EGNg//c752bUmnMD0tnaNGTaEOdEANg73Eo=; b=sUF6JAlgtTmoqE/o1yi/N5KbzrrxhgkgkuhlwT42VtuOLCUOKywnL8rnE2SUT7WWeYmULO0ZMI/Ti/Az+Sqa09yR1oRGFMlpikiNQ3EMMj2RiEv8t7W3RL9W12I/wQY8vi4TvqU2YRVNvnYYzJITaU/PUdAXcmPCA5UyEOglAFw= X-Mailgun-Sid: WyJkZWU4NyIsInRqcGh1aHNAZ21haWwuY29tIiwiNjNhZjVkIl0= X-Feedback-Id: postmaster@mg-d0.substack.com:post:6148c7d8a45790427cda307f:mailgun Received: by a5146f576da0e5ef239573da32e4a358caa032b9aad45b1d6ae3c44923c186fe with HTTP id 69f75e9e90397ad8d3935d46; Sun, 03 May 2026 14:41:33 GMT X-Mailgun-Sending-Ip: 159.112.244.34 Mime-Version: 1.0 Content-Type: multipart/alternative; boundary="7066191c55e281990e567527e0aab17389500f031ae5d090955d77cfc67d" Subject: A Molecular Stapler Could Make GLP-1 Drugs Last Longer. Scientists Borrowed It From Bacteria. From: Dave Knapp from On The Pen To: tjphuhs@gmail.com X-Mailgun-Tag: post X-Mailgun-Track-Clicks: false Message-Id: <20260503144057.3.8ab476f6d3c0f083@mg-d0.substack.com> Date: Sun, 3 May 2026 14:40:57 +0000 Feedback-Id: post-196317432:cat-post:pub-4808993:substack Sender: Dave Knapp from On The Pen References: In-Reply-To: Reply-To: Dave Knapp from On The Pen List-Owner: List-Url: List-Archive: List-Id: List-Post: List-Unsubscribe: List-Unsubscribe-Post: List-Unsubscribe=One-Click X-Mailgun-Variables: {"category": "post", "email_generated_at": "1777819293615", "is_freemail": "true", "post_audience": "everyone", "post_id": "196317432", "post_type": "newsletter", "pub_community_enabled": "true", "publication_id": "4808993", "subdomain": "onthepen", "user_id": "273622398"} --7066191c55e281990e567527e0aab17389500f031ae5d090955d77cfc67d Content-Type: text/plain; charset="utf-8" Content-Transfer-Encoding: quoted-printable View this post on the web at https://onthepen.substack.com/p/a-molecular-st= apler-could-make-glp The body has always known something drug developers are still learning: sha= pe matters. Not just the shape of a molecule as it enters a receptor, but the shape it = holds after hours in the bloodstream, after the body has done everything it= does to break things down. For the millions of people on semaglutide, tirz= epatide, or retatrutide, the drugs work. But the question researchers keep = returning to is whether they can work better, last longer, and hold their s= hape more completely against the body=E2=80=99s own cleanup systems. A team at the University of Utah thinks a bacterial enzyme that almost no o= ne was paying attention to might be part of the answer. The lock, the key, and what happens to the key over time GLP-1 medications work like a key fitting into a lock. The receptor sitting= on your cells is the lock. The drug is the key. When the key fits precisel= y into the lock, it triggers a cascade of signals that reduce appetite, slo= w digestion, and help regulate blood sugar. The whole system depends on tha= t key holding its shape long enough to do its job. The problem is that the body is constantly trying to take the key apart. Pe= ptide drugs like semaglutide are short chains of amino acids, the same buil= ding blocks that make up proteins, and the body recognizes them as somethin= g to be digested and cleared. Drug manufacturers have gotten creative about= slowing that process. Semaglutide, for example, has a long fatty acid chai= n attached to it that helps it hitch a ride on a blood protein called album= in, buying it enough time to last a full week before the next dose. But eve= n with that protection, the body still attacks the drug from its tail end, = using enzymes called exoproteases that chew through the peptide chain start= ing at one end and working inward. The key, in other words, is always being= worn down. The goal is to make it more durable. What PapB does, and why researchers got excited The enzyme at the center of this research is called PapB. It comes from bac= teria, and it belongs to a class of natural molecular machines that bacteri= a use to sculpt small protein chains into closed ring shapes, a process cal= led macrocyclization. The way to picture it is this: instead of leaving the= tail end of the key exposed and vulnerable, PapB acts as a molecular stapl= er that loops the tail back and snaps it into a closed ring. An exoprotease= trying to attack from that end suddenly has nowhere to grab. The key holds= its shape longer. It stays in the lock. The scientific community knew PapB existed, but it was considered too finic= ky to be broadly useful as a drug development tool. The enzyme was believed= to require a specific recognition tag attached to any peptide it would wor= k on, a kind of molecular return address called a leader sequence. Without = that tag, PapB was thought to simply ignore the peptide. Using it in practi= ce therefore meant attaching the tag, running the stapling reaction, and th= en chemically cutting the tag back off, a process that added steps, added c= ost, and limited which peptides it could realistically be used on. The Utah team, led by chemist Vahe Bandarian, decided to test just how stri= ct that requirement actually was. They fed PapB peptides with the wrong tag= =2E Then peptides with a completely for= eign tag from an unrelated biological=20= system. Then peptides with no tag at all. In every case, PapB formed the ri= ng anyway. The leader sequence was not the strict gatekeeper the field had = assumed. As the authors wrote in ACS Bio and Med Chem Au in October 2025, P= apB turns out to be a =E2=80=9Cplug-and-play biocatalyst=E2=80=9D that work= s across a remarkably wide range of molecular inputs. Testing it directly on GLP-1 drug analogs Once the team established that PapB was far more flexible than expected, th= ey moved to the obvious next question for readers of On The Pen: would it w= ork on peptides that look like the GLP-1 drugs people are actually taking? They built close laboratory analogs of semaglutide, tirzepatide, and retatr= utide, preserving the pharmacologically active cores of each drug while lea= ving off the fatty acid chains used for extended release. To the tail end o= f each peptide, they attached a short additional sequence that PapB could r= ecognize and staple into a ring. When they added the enzyme, it completed t= he ring on all three analogs, every single time, with nothing left unreacte= d. In laboratory terms, that is a perfect result. That closed ring at the tail end of the peptide does several things worth u= nderstanding. It blocks the exoproteases that would otherwise begin dismant= ling the key from that end. It also stiffens the tail of the molecule, redu= cing the kind of loose molecular movement that can make a key fit less prec= isely into its lock. And it creates a new chemical attachment point that re= searchers could potentially use to carry additional modifications, whether = that means helping the drug last longer in the body, directing it toward sp= ecific tissues, or other improvements to how it behaves over time. Why this matters beyond the laboratory Living with obesity means living with a biology that resists change, not ou= t of stubbornness, but out of deep evolutionary programming the body mistak= es for survival. The drugs that have transformed treatment over the past se= veral years work because they speak a language the body already understands= =2E They do not force a door open. They fit the lock. What PapB could eventually contribute to that story is persistence. Every t= ime a GLP-1 drug breaks down faster than intended, every time the body clea= rs it before the next injection is due, there is a gap in that conversation= between drug and receptor. A ring at the tail of the key is a structural a= nswer to that gap. It is the key being given a shape the body cannot as eas= ily dissolve. That matters in a clinical sense for dosing and efficacy. It = matters in a human sense for the people whose lives are organized around in= jection day and whether the medication is still holding. Where things stand now Bandarian and co-author Karsten Eastman have disclosed the findings to the = University of Utah and co-founded a company called Sethera Therapeutics bui= lt around this enzyme platform. The research was funded by the National Ins= titute of General Medical Sciences, part of the National Institutes of Heal= th. This work is proof of concept, meaning it is a meaningful early step but no= t a finished drug. The GLP-1 analogs used in the experiments were stripped = of their fatty acid chains, so they are not identical to the medications cu= rrently on the market. Whether PapB can be applied to the full clinical com= pounds, and whether the ring-shaped structures it creates show meaningfully= better performance in animal studies or human trials, has not yet been est= ablished. Those are the questions that come next. What has been established is that an enzyme borrowed from bacteria, one the= field had largely set aside as too limited to be useful, works on almost a= nything researchers put in front of it. It can close a ring at the tail end= of the keys that have already changed how medicine thinks about obesity. T= he question now is whether that ring can help those keys stay in the lock a= little longer. Source: Pedigo JK et al. (2025). Leader-independent C-terminal modification= enables macrocyclic GLP-1-like peptides. ACS Bio & Med Chem Au. https://do= i.org/10.1021/acsbiomedchemau.5c00152 Unsubscribe https://substack.com/redirect/2/eyJlIjoiaHR0cHM6Ly9vbnRoZXBlbi5= zdWJzdGFjay5jb20vYWN0aW9uL2Rpc2FibGVfZW1haWw_dG9rZW49ZXlKMWMyVnlYMmxrSWpveU= 56TTJNakl6T1Rnc0luQnZjM1JmYVdRaU9qRTVOak14TnpRek1pd2lhV0YwSWpveE56YzNPREU1T= WprekxDSmxlSEFpT2pFNE1Ea3pOVFV5T1RNc0ltbHpjeUk2SW5CMVlpMDBPREE0T1Rreklpd2lj= M1ZpSWpvaVpHbHpZV0pzWlY5bGJXRnBiQ0o5Lk9LejFRSTlndmFQdmlBeGotdmN6dlYtV1R1Z0x= Bc3ZUdFBvRWZLTFFRQzgiLCJwIjoxOTYzMTc0MzIsInMiOjQ4MDg5OTMsImYiOnRydWUsInUiOj= I3MzYyMjM5OCwiaWF0IjoxNzc3ODE5MjkzLCJleHAiOjIwOTMzOTUyOTMsImlzcyI6InB1Yi0wI= iwic3ViIjoibGluay1yZWRpcmVjdCJ9.im_EJtMGamKE1oMLqJuV_km7mBYjy6biwWGH1At65W4= ? --7066191c55e281990e567527e0aab17389500f031ae5d090955d77cfc67d Content-Type: text/html; charset="utf-8" Content-Transfer-Encoding: quoted-printable = A Molecular Stapler Could Make GLP-1 Drugs Last Longer. Scientists Borrowed= It From Bacteria.=3D""
The body has always known something drug devel= opers are still learning: shape matters.
͏     ­T= 7;     ­͏     ­͏     &= #173;͏     ­͏     ­͏   =   ­͏     ­͏     ­͏= ;     ­͏     ­͏     &#= 173;͏     ­͏     ­͏   &= #8199; ­͏     ­͏     ­͏=     ­͏     ­͏     = 73;͏     ­͏     ­͏   &#= 8199; ­͏     ­͏     ­͏ =     ­͏     ­͏     = 3;͏     ­͏     ­͏   = 199; ­͏     ­͏     ­͏ &= nbsp;   ­͏     ­͏     ­= ;͏     ­͏     ­͏   Q= 99; ­͏     ­͏     ­͏ &n= bsp;   ­͏     ­͏     ­= ͏     ­͏     ­͏   ̳= 9; ­͏     ­͏     ­͏ &nb= sp;   ­͏     ­͏     ­&= #847;     ­͏     ­͏    = ; ­͏     ­͏     ­͏ &nbs= p;   ­͏     ­͏     ­&#= 847;     ­͏     ­͏    = ­͏     ­͏     ­͏  = ;   ­͏     ­͏     ­= 47;     ­͏     ­͏     = ­͏     ­͏     ­͏  =   ­͏     ­͏     ­T= 7;     ­͏     ­͏     &= #173;͏     ­͏     ­͏   =   ­͏     ­͏     ­͏= ;     ­͏     ­͏     &#= 173;͏     ­͏     ­͏   &= #8199; ­͏     ­͏     ­͏=     ­͏     ­͏     = 73;͏     ­͏     ­͏   &#= 8199; ­͏     ­͏     ­͏ =     ­͏     ­͏     = 3;͏     ­͏     ­͏   = 199; ­͏     ­͏     ­͏ &= nbsp;   ­͏     ­͏     ­= ;͏     ­͏     ­͏   Q= 99; ­͏     ­͏     ­͏ &n= bsp;   ­͏     ­͏     ­= ͏     ­͏     ­͏   ̳= 9; ­͏     ­͏     ­͏ &nb= sp;   ­͏     ­͏     ­&= #847;     ­͏     ­͏    = ; ­͏     ­͏     ­͏ &nbs= p;   ­͏     ­͏     ­&#= 847;     ­͏     ­͏    = ­͏     ­͏     ­͏  = ;   ­͏     ­͏     ­= 47;     ­͏     ­͏     = ­͏     ­͏     ­͏  =   ­͏     ­͏     ­T= 7;     ­͏     ­͏     &= #173;͏     ­͏     ­͏   =   ­͏     ­͏     ­͏= ;     ­͏     ­͏     &#= 173;͏     ­͏     ­͏   &= #8199; ­͏     ­͏     ­͏=     ­͏     ­͏     = 73;͏     ­͏     ­͏   &#= 8199; ­͏     ­͏     ­͏ =     ­͏     ­͏     = 3;͏     ­͏     ­͏   = 199; ­͏     ­͏     ­͏ &= nbsp;   ­͏     ­͏     ­= ;͏     ­͏     ­͏   Q= 99; ­͏     ­͏     ­͏ &n= bsp;   ­͏     ­͏     ­= ͏     ­͏     ­͏   ̳= 9; ­͏     ­͏     ­͏ &nb= sp;   ­
Forwarded this email= ? Subscribe here for more

A Molec= ular Stapler Could Make GLP-1 Drugs Last Longer. Scientists Borrowed It Fro= m Bacteria.

= =
On The Pen GLP-1 News
=
 
3D""
3D""<= /td>
3D""=
3D""
READ IN APP3D""
 
<= /div>
=

The body has always known something drug developers a= re still learning: shape matters.

Not just the shape of a m= olecule as it enters a receptor, but the shape it holds after hours in the = bloodstream, after the body has done everything it does to break things dow= n. For the millions of people on semaglutide, tirzepatide, or retatrutide, = the drugs work. But the question researchers keep returning to is whether t= hey can work better, last longer, and hold their shape more completely agai= nst the body’s own cleanup systems.

A team at the Uni= versity of Utah thinks a bacterial enzyme that almost no one was paying att= ention to might be part of the answer.

3D""

The loc= k, the key, and what happens to the key over time

= GLP-1 medications work like a key fitting into a lock. The receptor sitting= on your cells is the lock. The drug is the key. When the key fits precisel= y into the lock, it triggers a cascade of signals that reduce appetite, slo= w digestion, and help regulate blood sugar. The whole system depends on tha= t key holding its shape long enough to do its job.

The prob= lem is that the body is constantly trying to take the key apart. Peptide dr= ugs like semaglutide are short chains of amino acids, the same building blo= cks that make up proteins, and the body recognizes them as something to be = digested and cleared. Drug manufacturers have gotten creative about slowing= that process. Semaglutide, for example, has a long fatty acid chain attach= ed to it that helps it hitch a ride on a blood protein called albumin, buyi= ng it enough time to last a full week before the next dose. But even with t= hat protection, the body still attacks the drug from its tail end, using en= zymes called exoproteases that chew through the peptide chain starting at o= ne end and working inward. The key, in other words, is always being worn do= wn. The goal is to make it more durable.

What PapB = does, and why researchers got excited

The enzyme a= t the center of this research is called PapB. It comes from bacteria, and i= t belongs to a class of natural molecular machines that bacteria use to scu= lpt small protein chains into closed ring shapes, a process called macrocyc= lization. The way to picture it is this: instead of leaving the tail end of= the key exposed and vulnerable, PapB acts as a molecular stapler that loop= s the tail back and snaps it into a closed ring. An exoprotease trying to a= ttack from that end suddenly has nowhere to grab. The key holds its shape l= onger. It stays in the lock.

The scientific community knew = PapB existed, but it was considered too finicky to be broadly useful as a d= rug development tool. The enzyme was believed to require a specific recogni= tion tag attached to any peptide it would work on, a kind of molecular retu= rn address called a leader sequence. Without that tag, PapB was thought to = simply ignore the peptide. Using it in practice therefore meant attaching t= he tag, running the stapling reaction, and then chemically cutting the tag = back off, a process that added steps, added cost, and limited which peptide= s it could realistically be used on.

The Utah team, led by = chemist Vahe Bandarian, decided to test just how strict that requirement ac= tually was. They fed PapB peptides with the wrong tag. Then peptides with a= completely foreign tag from an unrelated biological system. Then peptides = with no tag at all. In every case, PapB formed the ring anyway. The leader = sequence was not the strict gatekeeper the field had assumed. As the author= s wrote in ACS Bio and Med Chem Au in October 2025, PapB turns out to be a = “plug-and-play biocatalyst” that works across a remarkably wide= range of molecular inputs.

Testing it directly on = GLP-1 drug analogs

Once the team established that = PapB was far more flexible than expected, they moved to the obvious next qu= estion for readers of On The Pen: would it work on peptides that look like = the GLP-1 drugs people are actually taking?

They built clos= e laboratory analogs of semaglutide, tirzepatide, and retatrutide, preservi= ng the pharmacologically active cores of each drug while leaving off the fa= tty acid chains used for extended release. To the tail end of each peptide,= they attached a short additional sequence that PapB could recognize and st= aple into a ring. When they added the enzyme, it completed the ring on all = three analogs, every single time, with nothing left unreacted. In laborator= y terms, that is a perfect result.

That closed ring at the = tail end of the peptide does several things worth understanding. It blocks = the exoproteases that would otherwise begin dismantling the key from that e= nd. It also stiffens the tail of the molecule, reducing the kind of loose m= olecular movement that can make a key fit less precisely into its lock. And= it creates a new chemical attachment point that researchers could potentia= lly use to carry additional modifications, whether that means helping the d= rug last longer in the body, directing it toward specific tissues, or other= improvements to how it behaves over time.

Why this= matters beyond the laboratory

Living with obesity= means living with a biology that resists change, not out of stubbornness, = but out of deep evolutionary programming the body mistakes for survival. Th= e drugs that have transformed treatment over the past several years work be= cause they speak a language the body already understands. They do not force= a door open. They fit the lock.

What PapB could eventually= contribute to that story is persistence. Every time a GLP-1 drug breaks do= wn faster than intended, every time the body clears it before the next inje= ction is due, there is a gap in that conversation between drug and receptor= =2E A ring at the tail of the key is a=20= structural answer to that gap. It is t= he key being given a shape the body cannot as easily dissolve. That matters= in a clinical sense for dosing and efficacy. It matters in a human sense f= or the people whose lives are organized around injection day and whether th= e medication is still holding.

Where things stand n= ow

Bandarian and co-author Karsten Eastman have di= sclosed the findings to the University of Utah and co-founded a company cal= led Sethera Therapeutics built around this enzyme platform. The research wa= s funded by the National Institute of General Medical Sciences, part of the= National Institutes of Health.

This work is proof of conce= pt, meaning it is a meaningful early step but not a finished drug. The GLP-= 1 analogs used in the experiments were stripped of their fatty acid chains,= so they are not identical to the medications currently on the market. Whet= her PapB can be applied to the full clinical compounds, and whether the rin= g-shaped structures it creates show meaningfully better performance in anim= al studies or human trials, has not yet been established. Those are the que= stions that come next.

What has been established is that an= enzyme borrowed from bacteria, one the field had largely set aside as too = limited to be useful, works on almost anything researchers put in front of = it. It can close a ring at the tail end of the keys that have already chang= ed how medicine thinks about obesity. The question now is whether that ring= can help those keys stay in the lock a little longer.

Source: Pedigo JK et al. (2025). Leader-independent C-terminal modification enables macrocyclic GLP-1-l= ike peptides. ACS Bio & Med Chem Au. https://doi.org/10.1021= /acsbiomedchemau.5c00152

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