After GLP-1: Injection Is No Longer the Barrier, and Peptide Drugs Enter a New Era
Injectables are no longer a dealbreaker, and peptide drugs are extending from weight loss into exercise mimetics and neural modulation. The scientist's caveat: outside GLP, the data is still thin, and the approval cycle can run 20 years.
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The industry consensus that ‘nobody wants a shot’ has been overturned
The pharmaceutical industry used to believe that outside life-or-death drugs like insulin, nobody would accept an injectable. The success of GLP-1 drugs demolished that assumption completely — to the point that some patients now prefer the injection over a pill. That reopened the entire field of peptide therapeutics, and with it the question: beyond GLP-1, what else is worth injecting into your own body?
— Jonathan LongThe peptide market looks like subprime: good and bad bundled and sold together
The label ‘peptide’ covers two completely different things at once. One is peptide hormones that genuinely exist in the body with well-defined receptors — insulin, growth hormone — where the evidence is strong. The other is synthetic sequences like BPC-157, of unclear provenance, with no receptor and no clinical trial evidence, yet sold in volume on the gray market. Long draws the analogy to the subprime crisis: mix quality assets in with junk, package them together, and investors can no longer tell the good from the bad.
— Jonathan LongThe 50 peptides in the textbook are only the tip of the iceberg
Textbooks list only about 50 well-defined peptide hormones. Modern mass spectrometry detects between 500 and 50,000 peptides in body fluids — at least an order of magnitude more than previously recognized, coming from organs and cell types that were not known to produce peptides at all. But detected does not mean functional: many may be nothing more than low-abundance flotsam, and some may hide the next insulin. The discovery window is wide open, but going from existence to demonstrated function remains a long process.
— Jonathan LongPeptides are like Lego, and multi-target drugs are built brick by brick
Peptides are amino acids arranged in a line, like Lego bricks, and can be modified one amino acid at a time. Ozempic is a super-stabilized version of natural GLP-1 after adding a lipid and swapping amino acids. Going further, Tirzepatide fuses the two hormones GLP and GIP into a single multi-target agonist molecule, described as a unimolecular polyagonist. The field is already discussing a ‘five-peptide super metabolic drug’ fusing five peptides, as well as conjugating peptides to antibodies to cut injection frequency to once every six months.
— Jonathan LongA molecule made by exercise can switch off appetite in the brain directly
Lac-Phe is produced by intestinal epithelial cells in response to exercise or metformin, travels to the hypothalamus, suppresses the appetite-promoting AGRP neurons and activates the appetite-suppressing POMC neurons — a complete gut-brain circuit regulating food intake. Long stresses that anorexigenic is merely the academic term for ‘appetite-suppressing’ and has nothing to do with anorexia; he also notes that appetite may be just one of the molecule's many effects, just as GLP-1's action was not about weight loss when it was first discovered.
— Jonathan LongMetformin's weight loss effect may be Lac-Phe doing the work
Metformin, a century-old drug, sharply raises Lac-Phe, which partly explains its weight loss effect. A Danish team has completed a phase one human trial of intravenous Lac-Phe infusion in about 30 healthy volunteers; the results have not yet been released. This is the first step toward the clinic for Lac-Phe. Long cautions that Lac-Phe today sits roughly where GLP sat in 1980, and an approved drug may still be decades away.
— Jonathan LongThe effects of exercise are being broken down into druggable molecules
Beyond Lac-Phe, another exercise-related molecule is Apelin — an exercise-induced peptide hormone that in preclinical work lowers body weight and food intake while preserving muscle. Bay Area startup BioAge is developing it as an exercise-mimetic therapy. At Stanford, Helen Blau's group is instead focused on the role of prostaglandin signaling in muscle regeneration. The national program MOTRPAC is systematically mapping the molecular signatures of exercise in animals and humans, and the human data is starting to come out.
— Jonathan LongNobody is regulating the synthetic peptides on the gray market
GLP was discovered in the 1980s, and the first drug, Byetta, was not approved until the early 2000s — a gap of about 20 years. For new molecules like Lac-Phe, the evidence has to accumulate along that same long path. Separately, neither the current FDA nor the USDA regulatory framework covers gray-market synthetic peptides. The historical lesson is dinitrophenol: an unregulated weight-loss drug discovered at Stanford in the 1930s that killed multiple people and ultimately gave rise to the FDA. If peptide products cause serious harm, entirely new federal regulatory infrastructure may be required.
— Jonathan LongIn their own words · checked verbatim
It's a little bit like the subprime mortgage crisis where you take good things, you mix it with bad things, you mash it all together and you can't tell what's good or bad anymore.
Jonathan Long9:22
I think that the way to think about peptides is these are like Lego blocks.
Jonathan Long24:55
because before you had Ozempic as a medicine, weight loss was a willpower thing.
Jonathan Long28:29
The best and most exciting time for a project is before you do an experiment.
Jonathan Long43:54
At the same time, beyond GLP, the data are very sparse.
Jonathan Long44:55
We are back in where GLP was in 1980, and we have to remember that timeline.
Jonathan Long46:13
Figures
| Amino acid range for a peptide | 5-50 | 5:53 |
| Number of cells in the human body | about 30 trillion | 6:22 |
| Number of classical peptide hormones | about 50 | 14:59 |
| Peptides detectable by mass spectrometry | about 500-50,000 | 15:54 |
| Participants in the Lac-Phe phase one trial | about 30 | 34:00 |
| MariTide injection frequency | once every 6 months | 22:52 |
| Gap from GLP's discovery to first approved drug | about 20 years | 44:56 |
| First GLP drug | Byetta (approved in the early 2000s) | 44:56 |
Glossary
- GLP-1 (glucagon-like peptide-1)
- A peptide hormone secreted by the gut that stimulates insulin secretion and suppresses appetite; the target of weight-loss drugs like Ozempic.
- Lac-Phe (lactoyl-phenylalanine)
- A peptide-type molecule produced in response to exercise or metformin that suppresses food intake via a gut-brain circuit.
- Unimolecular polyagonist
- Fusing several peptide hormones into one molecule that acts on multiple receptors at once, as in Tirzepatide.
- AGRP neurons (agouti-related peptide neurons)
- Appetite-promoting neurons in the hypothalamus whose activity Lac-Phe suppresses.
- POMC neurons (pro-opiomelanocortin neurons)
- Appetite-suppressing neurons in the hypothalamus that Lac-Phe activates.
- MOTRPAC (Molecular Transducers of Physical Activity Consortium)
- A US national program launched by the NIH to systematically map the molecular changes produced by exercise.
How to listen
Investors following the weight-loss drug and metabolic health space, biopharma practitioners who want to separate scientific evidence from gray-market bottom-fishing, and researchers in exercise and longevity.
Listeners already well versed in the GLP-1 background can skip roughly the first 10 minutes of introductory material.