Peptide Information
General Information of This Peptide
| Peptide ID |
PEP00134
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| Peptide Name |
sdhAACSf
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| Structure |
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| Sequence |
SDHAACSF
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| Peptide Type |
Cyclic
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| Receptor Name |
Kappa-type opioid receptor (OPRK1)
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Receptor Info | ||||
| PDC Transmembrane Types | Cell targeting peptides (CTPs) | |||||
| Formula |
C35H46N10O14S
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| Isosmiles |
[H]OC[C@@H]1NC(=O)SC[C@@H](C(=O)N[C@@H](CO[H])C(=O)N[C@@H](Cc2ccccc2)C(=O)O)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](Cc2cn([H])cn2)NC(=O)[C@H](CC(=O)O)NC1=O
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| InChI |
InChI=1S/C35H46N10O14S/c1-16-27(50)38-17(2)28(51)44-25(33(56)43-23(12-46)31(54)42-22(34(57)58)8-18-6-4-3-5-7-18)14-60-35(59)45-24(13-47)32(55)41-21(10-26(48)49)30(53)40-20(29(52)39-16)9-19-11-36-15-37-19/h3-7,11,15-17,20-25,46-47H,8-10,12-14H2,1-2H3,(H,36,37)(H,38,50)(H,39,52)(H,40,53)(H,41,55)(H,42,54)(H,43,56)(H,44,51)(H,45,59)(H,48,49)(H,57,58)/t16-,17-,20-,21-,22-,23-,24-,25-/m0/s1
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| InChIKey |
UCVACLNCLYKKFO-MMJFIDRCSA-N
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| Pharmaceutical Properties |
Molecule Weight
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862.876
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Polar area
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376.54
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Complexity
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862.2915672
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xlogp Value
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-5.0028
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Heavy Count
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60
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Rot Bonds
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15
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Hbond acc
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14
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Hbond Donor
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13
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Each Peptide-drug Conjugate Related to This Peptide
Full Information of The Activity Data of The PDC(s) Related to This Peptide
De Novo Cyclic Peptide (DNCP)-β-naloxamine (NalA) conjugates 4 [Investigative]
Revealed Based on the Cell Line Data
| Experiment 1 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | Pain | ||||
| Efficacy Data | Half Maximal Effect Concentration (EC50) |
1.0 ± 0.1 x 10-9 mol
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| Evaluation Method | Potency/efficacy cAMP assay | ||||
| MOA of PDC |
Here, we exploit the crystal structure of KOR bound to the dual KOR/delta-opioid receptor (DOR) epoxymorphinan opioid agonist MP11048 and use the Rosetta protein and peptide design software to computationally design peptide-small molecule conjugates targeting KOR. Utilizing the high affinity interaction of MP1104 with KOR as an anchor to initiate the design calculations, we seek to computationally design thioether cyclic peptides that interact with ECL2 and ECL3 of the receptor.
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| Description |
We obtained four DNCP--NalA conjugates (1-4); the conjugation of DNCP (35) and DNCP (36) was unsuccessful. DNCP--NalA conjugates (1-4) were pharmacologically characterized via radioligand binding and functional cAMP assays to investigate their affinity, potency and efficacy at the mouse KOR. The DNCP--NalA conjugates exhibited affinities in the low nanomolar range, with DNCP--NalA(1) being the strongest binder at KOR with a Ki value of 3.9 nM, as compared to -NalA, which has an affinity Ki of 72 nM. All four DNCP--NalA conjugates were full agonists at KOR (Emax = 89-101%), while -NalA alone was only a partial agonist with an EC50 of 130 nM and Emax of 61%. The most potent conjugates were DNCP--NalA(1) and (4) with EC50 values of 2.0 nM and 1.0 nM, respectively. DNCP--NalA(2) and DNCP--NalA(3) showed agonist activities at KOR with EC50 values of 7.5 and 14 nM in cAMP assay, respectively, while their Ki values were 31 and 24 nM in radioligand binding assay, respectively. Receptor reserve may account for this discrepancy between potency and affinity values of DNCP--NalA(2) and DNCP--NalA(4) which can be observed in functional GPCR assays with opioid receptors30. The higher potency and efficacy of the conjugates at KOR compared to -NalA can be attributed to interactions of the macrocycles with the ECL2 region as described later.
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| In Vitro Model | Normal | HEK-293T cell | CVCL_0063 | ||
References