Table 2 Strategic placement of charged residues in the C-terminal tail can enhance cellular activity and mitigate off-target effects
From: Design-rules for stapled peptides with in vivo activity and their application to Mdm2/X antagonists
Peptide | C-terminus (1st position is residue 14) | Binding | Solubility | Cell EC50 (4 hr, 0% FBS) (µM) | Cell EC50 (16 hr, 10% FBS) (µM) | Proliferation EC50 | Proliferation EC50 | Proliferation % inhibition at 50 µM |
|---|---|---|---|---|---|---|---|---|
KD (nM) | (µM) | HCT116 | Ca Ski | Ca Ski | ||||
(On-target) (µM) | (Off-target) (µM) | % | ||||||
MP-081 | -SA2-NH2 | 5.0 | 105 | 0.49 | 0.86 | 2.3 | 32.8 | 85.5 |
MP-688* | -A6-NH2 | 21.5 | N.D. | 0.16 | 1.3 | 12.0 | 45.1 | 53.4 |
ALRN-6924* | -A5-dA-NH2 | 2.46 | P.B. | 0.14 | 0.32 | 0.87 | 47.5 | 48.7 |
MP-032 | -A6-NH2 | 9.45 | P.B. | 0.14 | 0.24 | 0.96 | 26.6 | 47.5 |
MP-464 | -A5-dA-NH2 | 30.9 | 157 | 0.43 | 0.29 | 0.42 | >49.75 | 9.9 |
MP-8834 | -EA4-dA-NH2 | 1.1 | 167 | 1.0 | 3.4 | 1.4 | >49.75 | -3.2 |
MP-965 | -AEA3-dA-NH2 | 5.7 | 161 | 1.1 | 2.2 | 2.7 | >49.75 | 16.2 |
MP-833 | -A2EA2-dA-NH2 | 3.1 | 154 | 0.96 | 0.19 | 0.14 | >49.75 | -11.1 |
MP-835 | -A3EA-dA-NH2 | <1 | 162 | 0.65 | 0.82 | 0.55 | >49.75 | -10.3 |
MP-837 | -A4E-dA-NH2 | 5.7 | 160 | 0.76 | 1.67 | 0.66 | >49.75 | 8.6 |
MP-836 | -A5E-NH2 | <1 | 164 | 0.55 | 1.06 | 1.05 | >49.75 | 13.2 |
MP-897 | -(Gla)A4-dA-NH2 | <1 | 163 | 0.79 | 0.52 | 0.79 | >49.75 | -19.1 |
MP-060 | -A5F-NH2 | 2.1 | P.B. | 0.17 | 2.7 | 0.46 | >49.75 | 18.6 |
MP-228 | -A2FA2-dA-NH2 | 4.2 | 2 | 0.21 | 0.69 | 2.7 | 30.7 | 68.7 |
MP-040 | -(A2F)2-NH2 | 27.1 | P.B. | 0.036 | 0.75 | 1.22 | >49.75 | 4.4 |
MP-063 | -A2FA2-dF-NH2 | 56.0 | 9 | 0.11 | 2.13 | 2.78 | >49.75 | 24.0 |
MP-288 | -A2FA2-(aMe-F)-NH2 | 23.7 | 12 | 0.10 | 2.68 | 2.74 | >49.75 | 5.3 |
MP-229 | -A2FA-(aMe-E)-F-NH2 | 4.8 | 153 | 0.20 | 0.21 | 2.32 | 19.9 | 102.7 |
MP-802 | -((hS)2F)2-NH2 (early isomer) | 7.4 | P.B. | 0.23 | 0.75 | 4.58 | 19.1 | 95.2 |
MP-803 | -((hS)2F)2-NH2 (late isomer) | 121.3 | 1 | 0.45 | 2.49 | 2.03 | 27.0 | 84.5 |
