After GLP-1: Injections Are No Longer a Barrier, Peptide Drugs Enter a New Era
Injectable drugs are no longer a barrier; peptide drugs are expanding from weight loss to exercise mimetics, neural regulation, and beyond. Scientists caution: outside GLP, data are still sparse, and approval cycles could take up to 20 years.
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The industry consensus that 'nobody wants injections' has been overturned
The pharmaceutical industry used to believe that, apart from life-or-death drugs like insulin, nobody would accept injectable medications. The success of GLP-1 drugs has completely overturned this assumption, and some patients even prefer injections over oral forms. As a result, the entire field of peptide therapeutics has been reopened, and the question becomes: besides GLP-1, what else is worth injecting into your body?
— Jonathan LongThe peptide market is like subprime: good and bad are packaged together
The peptide label covers two completely different categories: one is peptide hormones that truly exist in the body with clear receptors, such as insulin and growth hormone, with high levels of evidence; the other is synthetic sequences like BPC-157, of unknown origin, lacking receptors and clinical trial evidence, yet widely sold in the gray market. Long compares this to the subprime crisis: bundling high-quality assets with junk so that investors cannot tell good from bad.
— Jonathan LongThe ~50 textbook peptides are just 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 known—originating from organs and cells not previously known to produce peptides. But detection does not equal function: many may be low-abundance flotsam, but some could hide the next insulin. The discovery window is wide open, but moving from existence to validated function remains a long process.
— Jonathan LongPeptides are like LEGO: multi-target drugs are built piece by piece
Peptides are linear chains of amino acids, like LEGO bricks, and can be modified one amino acid at a time. Ozempic is a super-stabilized version of natural GLP-1 with added lipids and amino acid substitutions. Further, Tirzepatide fuses two hormones, GLP and GIP, into a single-molecule multi-target agonist, known as a unimolecular polyagonist. The industry is already discussing a 'five-peptide super metabolic drug' that fuses five peptides, as well as conjugating peptides to antibodies to reduce injection frequency to once every six months.
— Jonathan LongA molecule produced by exercise can directly switch off the brain's appetite switch
Lac-Phe is produced by gut epithelial cells in response to exercise or metformin, enters the hypothalamus, inhibits appetite-promoting AGRP neurons, and activates appetite-suppressing POMC neurons, forming a complete 'gut-brain' feeding regulation circuit. Long emphasizes that 'anorexigenic' is just the academic term for 'appetite-suppressing' and has nothing to do with anorexia; also, Lac-Phe may be just one of many effects of a molecule, just as GLP-1's initial discovered role was not weight loss.
— Jonathan LongMetformin's weight loss may be mediated by Lac-Phe
Metformin, a century-old drug, significantly raises Lac-Phe, partially explaining its weight-loss effects. A Danish team has completed a Phase 1 human trial of intravenous Lac-Phe infusion in about 30 healthy volunteers; results have not yet been published. This is the first step toward clinical use for Lac-Phe. Long cautions that Lac-Phe is currently in a position similar to GLP in 1980, and it may take decades before a drug is approved.
— Jonathan LongExercise effects are being broken down into druggable molecules
Beyond Lac-Phe, exercise-related molecules include Apelin—an exercise-induced peptide hormone that in preclinical studies reduces body weight and food intake while preserving muscle. Bay Area startup BioAge is developing it as an exercise mimetic therapy. Stanford's Helen Blau team focuses on prostaglandin signaling in muscle regeneration. The national project MOTRPAC is systematically mapping the exercise-induced molecular atlas in animals and humans, with human data beginning to be released.
— Jonathan LongNo agency regulates synthetic peptides in 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, data accumulation must follow the same long path. Meanwhile, current FDA and USDA regulatory frameworks do not cover gray-market synthetic peptides. The historical lesson is dinitrophenol: an unregulated weight-loss drug discovered at Stanford in the 1930s caused multiple deaths and eventually led to the creation of the FDA. If peptide products cause serious harm, an entirely new federal regulatory infrastructure may be needed.
— 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
| Peptide amino acid range | 5-50 | 5:53 |
| Number of human cells | ~30 trillion | 6:22 |
| Number of classic peptide hormones | ~50 | 14:59 |
| Peptides detectable by mass spectrometry | ~500-50,000 | 15:54 |
| Lac-Phe Phase 1 trial participants | ~30 | 34:00 |
| MariTide injection frequency | every 6 months | 22:52 |
| Interval from GLP discovery to first drug approval | ~20 years | 44:56 |
| First GLP drug | Byetta (approved in 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; it is the target of weight-loss drugs like Ozempic.
- Lac-Phe / lactate-phenylalanine
- A peptide-like molecule induced by exercise or metformin that suppresses food intake via a gut-brain circuit.
- Unimolecular polyagonist
- A single molecule that fuses multiple peptide hormones to act on multiple receptors, such as Tirzepatide.
- AGRP neurons / agouti-related peptide neurons
- Hypothalamic neurons that promote appetite; Lac-Phe inhibits their activity.
- POMC neurons / proopiomelanocortin neurons
- Hypothalamic neurons that suppress appetite; Lac-Phe activates them.
- MOTRPAC / Molecular Transducers of Physical Activity Consortium
- A national project initiated by the US NIH to systematically map molecular changes induced by exercise.
How to listen
Investors focused on weight-loss drugs and metabolic health, biopharma professionals who want to separate scientific evidence from gray-market bottom-fishing, and exercise and longevity researchers.
Listeners already familiar with GLP-1 background can skip the first ~10 minutes of basic introduction.