Table 2.
Effects of disulfide replacement on α-conotoxin sequences.
| Replacement Strategy | Conotoxin (Targeted Bridge) | Primary Receptor Target | Improved In Vitro Activity? | Retained Native Structure? | Reduced Disulfide Scrambling? | Improved Plasma Stability? | Ref |
|---|---|---|---|---|---|---|---|
| Diselenide | MI (3–13) | (α1)2β1δγ nAChR | ✓ | n.r. | n.r. | n.r. | [83] |
| AuIB (2–8) | α3β4 nAChR | ✓ | ✓ a,b | ✓ | ≈ | [83] | |
| AuIB (3–15) | α3β4 nAChR | ✓ | ✓ a,b | ✓ | ≈ | [83] | |
| ImI (2–8) | α7 nAChR | ✓ | ✓ a,c | ✓ | ✓ | [79,83] | |
| ImI (3–12) | α7 nAChR | ✓ | ✓ a,c | ✓ | ✓ | [79,83] | |
| ImI (2–8,3–12) | α7 nAChR | ✓ | ✓ a,c | ✓ | ✓ | [79] | |
| Vc1.1 (2–8) | α3β4 nAChR | ✓ | n.r. | n.r. | n.r. | [83] | |
| (A10L)-PnIA (2–8) | α7 nAChR | ≈ | n.r. | n.r. | n.r. | [83] | |
| (A10L)-PnIA (3–16) | α7 nAChR | n.r. | ✓ d | n.r. | n.r. | [83] | |
| Triazole | GI (2–7) | muscle nAChR | ✗ | n.r. | ✓ i | n.r. | [98] |
| GI (3–16) | muscle nAChR | ✓ | n.r. | ✓ i | n.r. | [98] | |
| Thioether | GI (2–7,3–16) | muscle nAChR | ✗ | n.r. | ✓ i | n.r. | [101] |
| ImI (2–8) | α7 nAChR | ✗ | ✓ c | ✓ i | n.r. | [102] | |
| ImI (3–12) | α7 nAChR | ≈ | ✓ c | ✓ i | n.r. | [102] | |
| ImI (2–8,3–12) | α7 nAChR | ✗ | ✓ b | ✓ i | n.r. | [102] | |
| Lactam | (des-Glu1)-GI (2–7) | undefined | ✗ | n.r. | ✓ i | n.r | [103] |
| (des-Glu1)-GI (3–16) | undefined | ≈ | n.r. | ✓ i | n.r. | [103] | |
| SI (2–7) e | α2βγδ nAChR | ✗ | n.r. | ✓ i | n.r. | [104] | |
| SI (2–7) f | α2βγδ nAChR | ✗ | n.r. | ✓ i | n.r. | [104] | |
| SI (3–13) e | α2βγδ nAChR | ✓ | n.r. | ✓ i | n.r. | [104] | |
| SI (3–13) f | α2βγδ nAChR | ✗ | n.r. | ✓ i | n.r. | [104] | |
| Dicarba | ImI cis-(2–8) | α7 nAChR | ≈ | ✓ c | ✓ i | n.r. | [105] |
| ImI trans-(2–8) | α7 nAChR | ✗ | ✓ c | ✓ i | n.r. | [105] | |
| Vc1.1 cis-(2–8) | GABAB | ✓ g | ✓ c | ✓ i | n.r. | [84] | |
| Vc1.1 trans-(2–8) | GABAB | ✓ g | ✗ c | ✓ i | n.r. | [84] | |
| Vc1.1 cis-(3–16) | GABAB | ✗ h | ✓ b | ✓ i | n.r. | [84] | |
| Vc1.1 trans-(3–16) | GABAB | ✗ h | ✓ c | ✓ i | n.r. | [84] | |
| RgIA cis-(2–8) | GABAB | ✓ g | ✓ c | ✓ i | ✓ | [106] | |
| RgIA trans-(2–8) | GABAB | ✓ g | ✗ b | ✓ i | ✓ i | [106] | |
| RgIA cis-(3–16) | GABAB | ✗ h | ✓ c | ✓ i | ✓ i | [106] | |
| RgIA trans-(3–16) | GABAB | ✗ h | ✓ c | ✓ i | ✓ i | [106] |
a: Determined by CD analysis; b: determined by secondary NMR chemical shift analysis; c: full NMR structural determination (3D-structure); d: X-ray analysis; e: Glu/Lys; f: Lys/Glu; g: GABAB active, inactive at α9α10 nAChR; h: α9α10 nAChR active, inactive at GABAB; i: determined by inference; ≈: equivalent to parent sequence; n.r.=not reported.