Albumin binding half-life extension: difference between revisions
Diff·revision 7 → 8·01:15, 11 Dec 2024
Difference between revision 7 and revision 8 of Albumin binding half-life extension. 11 lines changed; the page grew by 1,046 bytes.
| Revision 7 — 09:54, 23 Nov 2024 NavboxNiko (talk) add the counter-regulatory glucagon point, sourced 3,310 bytes +153 | Revision 8 — 01:15, 11 Dec 2024 BetaCellBoyd (talk) the numbers in the lead disagreed with the body; body was right 4,356 bytes +1,046 | ||
|---|---|---|---|
| 21 | The equilibrium is what makes the approach work. If binding were irreversible the peptide would never reach its receptor; if it were too weak the depot effect would be negligible. Reported bound fractions for the marketed incretin analogues exceed 99%, meaning free drug is under 1% of total at any moment and the receptor sees a small, steady concentration rather than a peak.{{r|knudsen2019}} | 21 | The equilibrium is what makes the approach work. If binding were irreversible the peptide would never reach its receptor; if it were too weak the depot effect would be negligible. Reported bound fractions for the marketed incretin analogues exceed 99%, meaning free drug is under 1% of total at any moment and the receptor sees a small, steady concentration rather than a peak.{{r|knudsen2019}} |
| 22 | 22 | ||
| + | 23 | == Design variables == | |
| + | 24 | | Variable | Liraglutide | Semaglutide | Effect of the change | | |
| + | 25 | |---|---|---|---| | |
| + | 26 | | Fatty acid | C-16 monoacid | C-18 diacid | Diacid binds more tightly | | |
| + | 27 | | Spacer | γ-Glu | γ-Glu plus two OEG units | Distance and flexibility | | |
| + | 28 | | Attachment | Lys26 | Lys26, with Arg34 substitution | Prevents acylation at the wrong lysine | | |
| + | 29 | | Protease resistance | None added | Aib at position 8 | DPP-4 resistance | | |
| + | 30 | | Resulting half-life | ≈13 h | ≈165 h | Daily to weekly dosing | | |
| + | 31 | ||
| + | 32 | The progression from the first to the second is instructive: three changes acting together produced roughly a twelvefold extension, and no single one of them would have sufficed. The terminal carboxylate of the diacid increases albumin affinity substantially; the OEG spacer holds the peptide away from the albumin surface so that receptor binding is not sterically impeded; the Aib substitution removes the [[Dipeptidyl peptidase-4|DPP-4]] cleavage site that would otherwise have become rate-limiting once renal clearance was slowed.{{r|lau2015}} | |
| + | 33 | ||
| 23 | == References == | 34 | == References == |
| 24 | {{reflist}} | 35 | {{reflist}} |