Small molecule vs peptide GLP-1 agonists — binding affinity comparison

PeptideChemSF said:

Oral semaglutide is absorbed in the stomach with the help of SNAC, which locally raises pH and protects the peptide long enough to cross.

No disagreement with PeptideChemSF. One condition attached. Orforglipron is the more interesting oral story because it is not a peptide at all. Being a small molecule it does not need SNAC, does not need the fasting window, and has oral bioavailability in the tens of percent rather than about one.

PeptideChemSF said:

Oral semaglutide is absorbed in the stomach with the help of SNAC, which locally raises pH and protects the peptide long enough to cross.

I do not accept that the fasting window is a minor inconvenience. Adherence data on daily orals with timing requirements is consistently worse than weekly injections, and a drug you take imperfectly is a lower dose than the one on the box.

Answering the narrow version, because the broad one does not have a single answer. The OASIS programme put 50mg oral in the same territory as 2.4mg injectable — around 15% mean weight loss — but it needed a dose 20 times larger to get there because almost none of the tablet is absorbed. The dose numbers are not comparable across routes and quoting them side by side confuses people.

FDA_TrackerJim said:

Orforglipron is the more interesting oral story because it is not a peptide at all.

Can confirm. Same sequence, different timescale. Posting only so the count is not one.