α-Conotoxin Peptidomimetics: Probing the Minimal Binding Motif for Effective Analgesia
Abstract
:1. Introduction
2. Therapeutic α-Conotoxin Development
3. Disulfide Replacement Strategies
3.1. The Importance of the Disulfide Bridge
3.2. Diselenide Bridges
3.3. Triazole
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] |
3.4. Thioether
3.5. Lactam Bridge
3.6. Dicarba Bridges
3.7. Disulfide-Based Target Tunability
4. Loop I Residue Analysis
4.1. N-Terminus
4.2. Gly1
4.3. Cys2 (and Cys8)
4.4. Cys3
4.5. Ser4
4.6. Asp5
4.7. Pro6
4.8. Arg7
5. Concluding Remarks
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Conotoxin | Sequence | Analgesia | UniProt ID | ||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| |||||||||||||||||||||
AnIB | G | G | C | C | S | H | P | A | C | A | A | N | N | Q | D | Y | C | * | n.r. | P0C1V7 | |
AuIB | - | G | C | C | S | Y | P | P | C | F | A | T | N | P | D | - | C | * | ✓ | P56640 | |
BuIA | - | G | C | C | S | T | P | P | C | A | V | L | Y | - | - | - | C | * | ✓ | P69657 | |
EpI | - | G | C | C | S | D | P | R | C | N | M | N | N | P | D | Y | C | * | n.r. | P56638 | |
GI | - | E | C | C | N | - | P | A | C | G | R | H | Y | S | - | - | C | * | ✓ | P01519 | |
ImI | - | G | C | C | S | D | P | R | C | A | W | R | - | - | - | - | C | * | ✗ | P50983 | |
Kn1.2 | P | G | C | C | N | N | P | A | C | V | K | H | R | - | - | - | C | G | n.r. | D4HRK7 | |
MI | G | R | C | C | H | - | P | A | C | G | K | N | Y | S | - | - | C | * | ✓ | P01521 | |
MII | - | G | C | C | S | N | P | V | C | H | L | E | H | S | N | L | C | * | ✓ | P56636 | |
MrI.I | - | G | C | C | S | H | P | A | C | S | V | N | N | P | D | I | C | * | ✓ | Q6PTD1 | |
PeIA | - | G | C | C | S | H | P | A | C | S | V | N | H | P | E | L | C | * | ✓ | Q1L777 | |
[A10L]-PnIA | - | G | C | C | S | L | P | P | C | A | L | N | N | P | D | Y | C | * | n.r. | P50984 | |
Pu1.2 | G | G | C | C | S | Y | P | P | C | I | A | N | N | P | L | - | C | * | ✓ | A1X8D8 | |
Reg1d | - | G | C | C | S | D | P | R | C | K | H | E | - | - | - | - | C | * | n.r. | P85010 | |
RgIA | - | G | C | C | S | D | P | R | C | R | Y | R | - | - | - | - | C | R | ✓ | P0C1D0 | |
SI | - | I | C | C | N | - | P | A | C | G | P | K | Y | S | - | - | C | * | n.r. | P15471 | |
Tx1.2 | P | Q | C | C | S | H | P | A | C | N | V | D | H | P | E | I | C | * | n.r. | P0DPL9 | |
Vc1.1 | - | G | C | C | S | D | P | R | C | N | Y | D | H | P | E | I | C | * | ✓ | P69747 |
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Kennedy, A.C.; Belgi, A.; Husselbee, B.W.; Spanswick, D.; Norton, R.S.; Robinson, A.J. α-Conotoxin Peptidomimetics: Probing the Minimal Binding Motif for Effective Analgesia. Toxins 2020, 12, 505. https://doi.org/10.3390/toxins12080505
Kennedy AC, Belgi A, Husselbee BW, Spanswick D, Norton RS, Robinson AJ. α-Conotoxin Peptidomimetics: Probing the Minimal Binding Motif for Effective Analgesia. Toxins. 2020; 12(8):505. https://doi.org/10.3390/toxins12080505
Chicago/Turabian StyleKennedy, Adam C., Alessia Belgi, Benjamin W. Husselbee, David Spanswick, Raymond S. Norton, and Andrea J. Robinson. 2020. "α-Conotoxin Peptidomimetics: Probing the Minimal Binding Motif for Effective Analgesia" Toxins 12, no. 8: 505. https://doi.org/10.3390/toxins12080505