Signaling Modulation via Minimal C-Terminal Modifications of Apelin-13
Why this work is in the frame
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Bibliographic record
Abstract
Apelin is an endogenous peptide that is involved in many diseases such as cardiovascular diseases, obesity, and cancer, which has made it an attractive target for drug discovery. Herein, we explore the penultimate and final sequence positions of [Pyr 1 ]-apelin-13 (Ape13) via C-terminal N α -alkylated amide bonds and the introduction of positive charges, potentially targeting the allosteric sodium pocket, by assessing the binding affinity and signaling profiles at the apelin receptor (APJ). Synthetic analogues modified within this segment of Ape13 showed high affinity ( K i 0.12–0.17 nM vs Ape13 K i 0.7 nM), potent Gα i1 activation (EC 50 Gα i1 0.4–0.9 nM vs Ape13 EC 50 1.1 nM), partial agonist behavior disfavoring β-arrestin 2 recruitment for positively charged ligands (e.g., 49 ( SBL-AP-058 ), EC 50 β-arr2 275 nM, E max 54%) and high plasma stability for N -alkyl ligands ( t 1/2 > 7 h vs Ape13 t 1/2 0.5 h). Combining the benefits of the N α -alkylated amide bond with the guanidino substitution in a constrained ligand led to 63 ( SBL-AP-049 ), which displayed increased plasma stability ( t 1/2 5.3 h) and strong reduction of β-arrestin 2 signaling with partial maximal efficacy (EC 50 β-arr 864 nM, E max 48%), significantly reducing the hypotensive effect in vivo .
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.003 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it