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[209.85.220.41]) by mx.google.com with SMTPS id ada2fe7eead31-62c84e4bfccsor2606413137.0.2026.05.03.11.45.59 for (Google Transport Security); Sun, 03 May 2026 11:45:59 -0700 (PDT) Received-SPF: pass (google.com: domain of tjphuhs@gmail.com designates 209.85.220.41 as permitted sender) client-ip=209.85.220.41; Authentication-Results: mx.google.com; dkim=pass header.i=@gmail.com header.s=20251104 header.b=jCiDLHqg; spf=pass (google.com: domain of tjphuhs@gmail.com designates 209.85.220.41 as permitted sender) smtp.mailfrom=tjphuhs@gmail.com; dmarc=pass (p=NONE sp=QUARANTINE dis=NONE) header.from=gmail.com; dara=pass header.i=@gmail.com DKIM-Signature: v=1; a=rsa-sha256; c=relaxed/relaxed; d=gmail.com; s=20251104; t=1777833959; x=1778438759; dara=google.com; h=mime-version:subject:references:in-reply-to:message-id:to:from:date :from:to:cc:subject:date:message-id:reply-to; bh=uHQy8b0uOoSuYOur6vvr8e5VONpOOsOGA3mJ06OYZ7g=; b=jCiDLHqgQKYmxVtSDeXiPxjSXqr5x/QjHW9FcfwXGEXFI/FCQYaBM1/f8lKy+D9f73 gu9dQl3t5QLF2H6rVbvixkyqFeYbJqnG5VEutdiUS1y6RK6cg1UduH0i1GkTEJQ5DSRO ePTHHJwlS6qzOZgwv9WwjUBAu5KRFR9dS1dcyDttjqBKvoHzk56qja+GWv9n+qc6Mwl7 Fl2lx9kZYbGmJHIOBf8RpLJ9jHQt1eR22Cal1K+r4J7XcA98EYC6XBRHgfYNhzwyiCL9 XPfhomfflQMFhaIJlikWPsM7U1WVhRvBSqZ+rTNMp6FN9sYWN9zLBs0ttXcTdvBUxvC7 yDDQ== X-Google-DKIM-Signature: v=1; a=rsa-sha256; c=relaxed/relaxed; d=1e100.net; s=20251104; t=1777833959; x=1778438759; h=mime-version:subject:references:in-reply-to:message-id:to:from:date :x-gm-gg:x-gm-message-state:from:to:cc:subject:date:message-id :reply-to; bh=uHQy8b0uOoSuYOur6vvr8e5VONpOOsOGA3mJ06OYZ7g=; b=kp6NOAm4kdHDajpE3bb2m90KPp6z60BLpQDlLidNkaU508hAh2XaGBwI3Qw3TiMCjw VbP5jYdQJOufTBak6igECbm+8Tp+BvcMgOem1KMZcvK/norGxhSs5gqBiXAr8rnnJyZR gI4AUd1vmXc/XvcxxL/ZcMglbWlRqdC3/B7enY0zTEtrYOMsNTZQFhK+AwAC7xm75Cpe H/JATYxTEupqryAYNgiRhQJKlkVbEvNcbCaymuDo82E5XZ0hk51jUjLRmQTOLvAUZrxQ 5H1vG0Ckx5ZbFTydK1dyO2/M1Wzg7uBt7lbvLOdTpRBGcEziPZEb7NOOGsidEQewJGwB Knww== X-Gm-Message-State: AOJu0Yx23wKzhbHpWdNieOTDHdY2xqpBviWlK3og5O16uRvMf+YNZqSu IkDUzeSjFQWvJmFRDiXRiiow8OxNHGa1DPCEXOrT0odGLnX8xsih7ITP1oJOobIw X-Gm-Gg: AeBDiesxiarw530KzRWVMf6Ix0hxBHlwqnYA9GfJiple8DUf8+wrJCwPEv3nGpLMcV+ QtPteLlLBbdeQJunXHedboNTrLqBAnqLknzEhVitQQ0arIqEpCrGpxv7dpA1IAxmFtAMBZsQLtj kTcHrl2lNfe0U/sqd9/cQLUQ7jCs7cQ7zulEfz1KEqAQwNSgkdMfigUlI8JkwzcXwvA8zjw9jmu /7VUewPBYIm1aC/BQBpTBfLSihNIzVTXGcFkg2lwaaMQ8EIVq044M5Re4hygmLNILhIn/QTfz2Q jL7PRZwHciq6Qi4mF/IS2J999xDKreaxZ9wPXCc1pse8Tw4CO6WVMDhC+UqB/OXiLsFS6KNUkDb xeEoqnq8WK7N87iD2M1lwMiMxgJ+b9q+eTt5JZOunv2u8QI2F06JYOvzirMwmZRNDfwkbDKE5zc xODmBv888CkOz1+u/Ga8zzpfLzsQWPTUkbYuofDDFiH2Z/yg== X-Received: by 2002:a05:6102:84ce:10b0:61c:5310:e9d6 with SMTP id ada2fe7eead31-62de41c2543mr1359649137.27.1777833958590; Sun, 03 May 2026 11:45:58 -0700 (PDT) Return-Path: Received: from [192.168.1.81] ([97.106.1.95]) by smtp.gmail.com with ESMTPSA id a1e0cc1a2514c-95ce0b63bb8sm4337967241.12.2026.05.03.11.45.55 for (version=TLS1_2 cipher=ECDHE-ECDSA-AES128-GCM-SHA256 bits=128/128); Sun, 03 May 2026 11:45:57 -0700 (PDT) Date: Sun, 3 May 2026 14:45:39 -0400 From: tjphuhs@gmail.com To: "=?utf-8?Q?oc.tjphuhs=40gmail.com?=" Message-ID: <82fec611-627f-4acb-b536-b0e5e07896a1@Spark> In-Reply-To: <20260503144057.3.8ab476f6d3c0f083@mg-d0.substack.com> References: <20260503144057.3.8ab476f6d3c0f083@mg-d0.substack.com> Subject: Fwd: A Molecular Stapler Could Make GLP-1 Drugs Last Longer. Scientists Borrowed It From Bacteria. X-Readdle-Message-ID: 82fec611-627f-4acb-b536-b0e5e07896a1@Spark MIME-Version: 1.0 Content-Type: multipart/alternative; boundary="69f797e3_1db72871_d8c9" --69f797e3_1db72871_d8c9 Content-Type: text/plain; charset="utf-8" Content-Transfer-Encoding: quoted-printable Content-Disposition: inline ---------- =46orwarded message ---------- =46rom: Dave Knapp from On The Pen Date: May 3, 2026 at 10:41=E2=80=AFAM -0400 To: tjphuhs=40gmail.com Subject: A Molecular Stapler Could Make GLP-1 Drugs Last Longer. Scientis= ts Borrowed It =46rom Bacteria. > The body has always known something drug developers are still learning:= shape matters. > =CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0= =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2= =AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2= =A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87= =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F= =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80= =87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD= =8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2= =80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD= =CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0= =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2= =AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F 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=C2=A0 =E2=80=87 =C2= =AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2= =A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87= =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F= =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80= =87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD= =8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2= =80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD= =CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0= =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2= =AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2= =A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87= =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F= =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80= =87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD= =8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2= =80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD= =CD=8F =C2=A0 =E2=80=87 =C2=AD=CD=8F =C2=A0 =E2=80=87 =C2=AD > =46orwarded this email=3F Subscribe here for more > A Molecular Stapler Could Make GLP-1 Drugs Last Longer. Scientists Borr= owed It =46rom Bacteria. > On The Pen GLP-1 News > May 3 > > READ IN APP > > The body has always known something drug developers are still learning:= shape 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 everyth= ing it does to break things down. =46or the millions of people on semaglu= tide, tirzepatide, or retatrutide, the drugs work. But the question resea= rchers keep returning to is whether they can work better, last longer, an= d hold their shape 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 one 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 sit= ting on your cells is the lock. The drug is the key. When the key fits pr= ecisely into the lock, it triggers a cascade of signals that reduce appet= ite, slow digestion, and help regulate blood sugar. The whole system depe= nds on that key holding its shape long enough to do its job. > The problem is that the body is constantly trying to take the key apart= . Peptide drugs like semaglutide are short chains of amino acids, the sam= e building blocks that make up proteins, and the body recognizes them as = something to be digested and cleared. Drug manufacturers have gotten crea= tive about slowing that process. Semaglutide, for example, has a long fat= ty acid chain attached to it that helps it hitch a ride on a blood protei= n called albumin, buying it enough time to last a full week before the ne= xt dose. But even with that protection, the body still attacks the drug f= rom its tail end, using enzymes called exoproteases that chew through the= peptide chain starting 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= bacteria, and it belongs to a class of natural molecular machines that b= acteria use to sculpt small protein chains into closed ring shapes, a pro= cess called macrocyclization. The way to picture it is this: instead of l= eaving the tail end of the key exposed and vulnerable, PapB acts as a mol= ecular stapler that loops the tail back and snaps it into a closed ring. = An exoprotease trying to attack from that end suddenly has nowhere to gra= b. The key holds its shape longer. It stays in the lock. > The scientific community knew PapB existed, but it was considered too f= inicky to be broadly useful as a drug development tool. The enzyme was be= lieved to require a specific recognition tag attached to any peptide it w= ould work 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 practice therefore meant attaching the tag, running the stapling re= action, and then chemically cutting the tag back off, a process that adde= d steps, added cost, and limited which peptides it could realistically be= used on. > The Utah team, led by chemist Vahe Bandarian, decided to test just how = strict that requirement actually was. They fed PapB peptides with the wro= ng tag. Then peptides with a completely foreign tag from an unrelated bio= logical system. Then peptides with no tag at all. In every case, PapB for= med the ring anyway. The leader sequence was not the strict gatekeeper th= e field had assumed. As the authors wrote in ACS Bio and Med Chem Au in O= ctober 2025, PapB turns out to be a =E2=80=9Cplug-and-play biocatalyst=E2= =80=9D 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 question for readers of On The Pen: woul= d it work on peptides that look like the GLP-1 drugs people are actually = taking=3F > They built close laboratory analogs of semaglutide, tirzepatide, and re= tatrutide, preserving the pharmacologically active cores of each drug whi= le leaving off the fatty acid chains used for extended release. To the ta= il end of each peptide, they attached a short additional sequence that Pa= pB could recognize and staple into a ring. When they added the enzyme, it= completed the ring on all three analogs, every single time, with nothing= left unreacted. In laboratory terms, that is a perfect result. > That closed ring at the tail end of the peptide does several things wor= th understanding. It blocks the exoproteases that would otherwise begin d= ismantling the key from that end. It also stiffens the tail of the molecu= le, reducing the kind of loose molecular movement that can make a key fit= less precisely into its lock. And it creates a new chemical attachment p= oint that researchers could potentially use to carry additional modificat= ions, whether that means helping the drug last longer in the body, direct= ing it toward specific tissues, or other improvements to how it behaves o= ver time. > Why this matters beyond the laboratory > Living with obesity means living with a biology that resists change, no= t out of stubbornness, but out of deep evolutionary programming the body = mistakes for survival. The drugs that have transformed treatment over the= past several years work because they speak a language the body already u= nderstands. They do not force a door open. They fit the lock. > What PapB could eventually contribute to that story is persistence. Eve= ry time a GLP-1 drug breaks down faster than intended, every time the bod= y clears it before the next injection is due, there is a gap in that conv= ersation between drug and receptor. A ring at the tail of the key is a st= ructural answer to that gap. It is the key being given a shape the body c= annot as easily dissolve. That matters in a clinical sense for dosing and= efficacy. It matters in a human sense for the people whose lives are org= anized around injection 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 Therapeuti= cs built around this enzyme platform. The research was funded by the Nati= onal Institute of General Medical Sciences, part of the National Institut= es of Health. > This work is proof of concept, meaning it is a meaningful early step bu= t not a finished drug. The GLP-1 analogs used in the experiments were str= ipped of their fatty acid chains, so they are not identical to the medica= tions currently on the market. Whether PapB can be applied to the full cl= inical compounds, and whether the ring-shaped structures it creates show = meaningfully better performance in animal studies or human trials, has no= t yet been established. 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 al= most anything 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. The question now is whether that ring can help those keys stay i= n the lock a little longer. > Source: Pedigo JK et al. (2025). Leader-independent C-terminal modifica= tion enables macrocyclic GLP-1-like peptides. ACS Bio & Med Chem Au. http= s://doi.org/10.1021/acsbiomedchemau.5c00152 > VISIT OUR SPONSORS=21 > You=E2=80=99re currently a free subscriber to On The Pen. =46or premium= access to insider articles, upgrade to paid. > Upgrade to paid > > Share > > > Like > Comment > Restack > > =C2=A9 2026 David Knapp > On The Pen, PO Box 541, Cedar =46alls, IA 50613 > Unsubscribe --69f797e3_1db72871_d8c9 Content-Type: text/html; charset="utf-8" Content-Transfer-Encoding: quoted-printable Content-Disposition: inline
---------- =46orwarded message ----= ------
=46rom: Dave Knapp from On The Pen <onthepen=40substack.com>=
Date: May 3, 2026 at 10:41=E2=80=AFAM -0400
To: tjphuhs=40gmail.com
Subject: A Molecular Stapler Could Make GLP-1 Drugs Last Longer. S= cientists Borrowed It =46rom Bacteria.

3D=22=22
The body has always known something drug developers are still le= arning: shape matters.
=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD= =CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23= 160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80= =87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD= =CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23= 160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80= =87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD= =CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23= 160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80= =87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD= =CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23= 160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80= =87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD= =CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23= 160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80= =87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD= =CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23= 160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80= =87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD= =CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23= 160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80= =87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD= =CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23= 160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80= =87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD= =CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23= 160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80= =87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD= =CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23= 160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80= =87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD= =CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23= 160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80= =87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD= =CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23= 160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80= =87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD= =CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23= 160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80= =87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD= =CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23= 160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80= =87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD= =CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23= 160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80= =87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD= =CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23= 160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80= =87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD= =CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23= 160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80= =87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD= =CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23= 160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80= =87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD= =CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23= 160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80= =87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD= =CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23= 160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80= =87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD= =CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23= 160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80= =87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD= =CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23= 160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80= =87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD= =CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23= 160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80= =87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD= =CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23= 160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80= =87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD= =CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23= 160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80= =87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD= =CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23= 160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80= =87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD= =CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23= 160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80= =87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD= =CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23= 160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80= =87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD= =CD=8F &=23160; =E2=80=87 =C2=AD=CD=8F &=23160; =E2=80=87 =C2=AD
=46orwarded this email=3F Subscribe here for more=

A M= olecular Stapler Could Make GLP-1 Drugs Last Longer. Scientists Borrowed = It =46rom Bacteria.

On The Pen GLP-1 News
&=23160;=
3D=22=22
3D=22=22
3D=22=22
3D=22=22=
READ IN APP3D=
&=23160;=

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

Not just the shape of a molecule as it enters a recept= or, but the shape it holds after hours in the bloodstream, after the body= has done everything it does to break things down. =46or the millions of = people on semaglutide, tirzepatide, or retatrutide, the drugs work. But t= he question researchers keep returning to is whether they can work better= , last longer, and hold their shape more completely against the body=E2=80= =99s own cleanup systems.

A team at the University of Utah thinks a bacterial en= zyme that almost no one was paying attention to might be part of the answ= er.

3D=22=22

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. Whe= n the key fits precisely into the lock, it triggers a cascade of signals = that reduce appetite, slow digestion, and help regulate blood sugar. The = whole system depends on that key holding its shape long enough to do its = job.

The problem is that the body is constantly trying to t= ake the key apart. Peptide drugs like semaglutide are short chains of ami= no acids, the same building blocks that make up proteins, and the body re= cognizes them as something to be digested and cleared. Drug manufacturers= have gotten creative about slowing that process. Semaglutide, for exampl= e, has a long fatty acid chain attached to it that helps it hitch a ride = on a blood protein called albumin, buying it enough time to last a full w= eek before the next dose. But even with that protection, the body still a= ttacks the drug from its tail end, using enzymes called exoproteases that= chew through the peptide chain starting at one end and working inward. T= he key, in other words, is always being worn down. The goal is to make it= more durable.

What PapB does, and why researchers got excite= d

The enzyme at the center of this research is called Pa= pB. It comes from bacteria, and it belongs to a class of natural molecula= r machines that bacteria use to sculpt small protein chains into closed r= ing shapes, a process called macrocyclization. The way to picture it is t= his: instead of leaving the tail end of the key exposed and vulnerable, P= apB acts as a molecular stapler that loops the tail back and snaps it int= o a closed ring. An exoprotease trying to attack from that end suddenly h= as 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 finicky 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 work on, a kind of molecular return address called = a leader sequence. Without that tag, PapB was thought to simply ignore th= e peptide. Using it in practice therefore meant attaching the tag, runnin= g the stapling reaction, and then chemically cutting the tag back off, a = process that added steps, added cost, and limited which peptides it could= realistically be used on.

The Utah team, led by chemist Vahe Bandarian, decided = to test just how strict that requirement actually was. They fed PapB pept= ides with the wrong tag. Then peptides with a completely foreign tag from= an unrelated biological system. Then peptides with no tag at all. In eve= ry case, PapB formed the ring anyway. The leader sequence was not the str= ict gatekeeper the field had assumed. As the authors wrote in ACS Bio and= Med Chem Au in October 2025, PapB turns out to be a =E2=80=9Cplug-and-pl= ay biocatalyst=E2=80=9D that works across a remarkably wide range of mole= cular inputs.

Testing it directly on GLP-1 drug analogs

Once the team established that PapB was far more flexi= ble than expected, they moved to the obvious next question for readers of= On The Pen: would it work on peptides that look like the GLP-1 drugs peo= ple are actually taking=3F

They built close laboratory analogs of semaglutide, ti= rzepatide, and retatrutide, preserving the pharmacologically active cores= of each drug while leaving off the fatty acid chains used for extended r= elease. To the tail end of each peptide, they attached a short additional= sequence that PapB could recognize and staple into a ring. When they add= ed the enzyme, it completed the ring on all three analogs, every single t= ime, with nothing left unreacted. In laboratory terms, that is a perfect = result.

That closed ring at the tail end of the peptide does s= everal things worth understanding. It blocks the exoproteases that would = otherwise begin dismantling the key from that end. It also stiffens the t= ail of the molecule, reducing the kind of loose molecular movement that c= an make a key fit less precisely into its lock. And it creates a new chem= ical attachment point that researchers could potentially use to carry add= itional modifications, whether that means helping the drug 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 r= esists change, not out of stubbornness, but out of deep evolutionary prog= ramming the body mistakes for survival. The drugs that have transformed t= reatment over the past several years work because they speak a language t= he 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 down faster than intended, e= very time the body clears it before the next injection is due, there is a= gap in that conversation between drug and receptor. A ring at the tail o= f the key is a structural answer to that gap. It is the key being given a= shape the body cannot as easily dissolve. That matters in a clinical sen= se for dosing and efficacy. It matters in a human sense for the people wh= ose lives are organized around injection day and whether the medication i= s 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 S= ethera Therapeutics built around this enzyme platform. The research was f= unded by the National Institute of General Medical Sciences, part of the = National Institutes of Health.

This work is proof of concept, meaning it is a meaning= ful early step but not a finished drug. The GLP-1 analogs used in the exp= eriments were stripped of their fatty acid chains, so they are not identi= cal to the medications currently on the market. Whether PapB can be appli= ed to the full clinical compounds, and whether the ring-shaped structures= it creates show meaningfully better performance in animal studies or hum= an trials, has not yet been established. Those are the questions that com= e next.

What has been established is that an enzyme borrowed f= rom bacteria, one the field had largely set aside as too limited to be us= eful, works on almost anything researchers put in front of it. It can clo= se a ring at the tail end of the keys that have already changed how medic= ine 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-like peptides. ACS Bio & Med Che= m Au. https://doi.org/10.1021/acsbiomedchemau.5c00152

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