Table 1 Peptide derivates designed to directly impact on aggregation and toxicity of αS. The peptide identifier number listed matches to numbers shown in Fig. 1 (green) to indicate for those known where they bind within αS and where within the aggregation profile they are thought to impact
From: Peptide-based approaches to directly target alpha-synuclein in Parkinson’s disease
Peptide Antagonists of αS Aggregation / Toxicity | ||||||
|---|---|---|---|---|---|---|
Peptide Name | Length | Sequence | Target αS Region/Species | Effect | Peptide Identifier | Reference |
aS1 − 25 | 25 | MDVFMKGLSKAKEGVVAAAEKTKQG | N-terminal lipid binding | < 80% reduction in lipid-induced ThT Fluorescence at 1:10 (αS:Peptide) | 1 | Meade 2023 [66] |
Retro-inverso βS36 | 10 | RTKSGVYLVG | 36–45 in βSyn. (highly conserved in αS) | > 98% reduction in ThT Fluorescence at 1:20 (αS:Peptide) 2.Drospsphila model overexpressing A53T αS mutant recovered 86% locomotion following peptide treatment. | 2 | Shaltiel-Karyo 2010 [83] |
αS36 − 46-PQQ | 11 | GVLYVGSKTKE | 36–42, p1 region | > 60% reduction in ThT Fluorescence at 1:10 (αS:Peptide) 2. Reduced toxicity of aS119 mutant by ~ 40% in U2-OS cells. | 3 | Yoshida 2013 [106] |
Tat-βsyn-degron | 25 | YGRKKRRQRRRRTKSGVYLVGRRRG | 36–45 in βSyn. (Highly conserved in αS) | Reduced αS levels over 24 h in M83 transgenic mice overexpressing A53T αS. | 4 | Jin 2021 [107] |
NTR-TP-L | 7 | GVLYVGS-Aib | p1 region | 98% reduction in ThT Fluorescence at 1:5 (αS:Peptide) 2. Restored 84% cell viability in Caco-2 MTT Cytotoxicity assays. | 5 | Horsley 2022 [67] |
NTR-TP-D | 7 | GVLYVGS-Aib | p1 region | 98% reduction in ThT Fluorescence at 1:5 (αS:Peptide) 2. Restored 88% cell viability in Caco-2 MTT Cytotoxicity assays. | 6 | Horsley 2022 [67] |
4554 W | 10 | KDGIVNGVKA | preNAC (αS45 − 54) | 1.>90% reduction in ThT Fluorescence at 1:1 (αS:Peptide) 2. Restored 80% cell viability in PC12 MTT Cytotoxicity assays. | 7 | Cheruvara 2015 [44] |
4654 W(N6A) | 9 | DGIVAGVKA | preNAC | 1. >98% reduction in ThT Fluorescence at 1:10 (αS:Peptide) 2. Restored 100% cell viability in SH-SY5Y MTT Cytotoxicity assays. | 8 | Meade 2021 [89] |
GQTYVLPG | 8 | GQTYVLPG | 46–53 preNAC | < 90% reduction in ThT Fluorescence at 1:40 (αS:Peptide) | 9 | Rezaeian 2017 [68] |
CP-2 | 6 | JWHSKL (Cyclic) J = Norleucine | NAC and N-Terminal | 1. ~70% reduction in ThT Fluorescence at 1:1 (αS:Peptide) 2. Improved cell viability by ~ 20% in PC12 MTT Cytotoxicity | 10 | Chemerovski-Glikman 2016 [85] |
S37 | 15 | GAVVWGVTAVKKKKK | 68–78 NACore | 1. >90% reduction in ThT Fluorescence at 1:10 (αS:Peptide) 2. Reducing αS seeding by ~ 60% | 11 | Sangwan 2020 [78] |
S61 | 22 | GAVVWGVTAVGRKKRRQRRRPQ | 68–78 NACore | 1. >80% reduction in ThT Fluorescence at 1:2 (αS:Peptide) 2. Reducing αS seeding by ~ 30% | 12 | Sangwan 2020 [78] |
S62 | 24 | GAVVWGVTAVKKGRKKRRQRRRPQ | 68–78 NACore | 1. >90% reduction in ThT Fluorescence at 1:1 (αS:Peptide) 2. Reducing αS seeding by ~ 80% | 13 | Sangwan 2020 [78] |
S71 | 22 | YGRKKRRQRRRAVVT (nme-Gly)VTAVAE | 68–78 NACore | 1. >70% reduction in ThT Fluorescence at 1:10 (αS:Peptide) 2. Reducing αS seeding by ~ 60% | 14 | Sangwan 2020 [78] |
KISVRV | 6 | KISVRV | 70–75 NAC | 1. <90% reduction in ThT Fluorescence at 1:5 (αS:Peptide) 2. Removed oligomer peak from SEC following 4-day incubation. | 15 | Rezaeian 2017 [68] |
T72P-6mer | 6 | PGVTAV | 72–77 NAC | < 90% reduction in ThT Fluorescence at 1:5 (αS:Peptide) | 16 | Soon Kim 2009 [74] |
71–76 | 6 | mVTGVTA VTGmVTA | NAC region | No inhibitory effect | 17 | Madine 2008 [55] |
77–82 | 6 | VAQKTmV VmAQKTV | NAC region | 1. 60% reduction in ThT Fluorescence at 1:1 (αS:Peptide) | 18 | Madine 2008 [55] |
NAC-TP-L | 6 | VAQKTV-Aib | NAC region | No inhibitory effect | 19 | Horsley 2022 [67] |
NAC-TP-D | 6 | VAQKTV-Aib | NAC region | 50% reduction in ThT Fluorescence at 1:5 (αS:Peptide) 2. Restored ~ 70% cell viability in Caco-2 MTT Cytotoxicity assays. | 20 | Horsley 2022 [67] |
PDpep1.3 | 12 | DEEIERQLKALG | C-terminus | PDpep1.3 reduced pS129 αS accumulation in striatum of rat model. | 21 | Nim 2023 [94] |
K84s | 25 | FLVWGCLRGSAIGECVVHGGPPSRH | Oligomers | 1. >75% reduction in ThT Fluorescence at 1:1 (αS:Peptide) 2. Reduced αS inclusion formation by ~ 20% in human neuroglioma cells (H4) | 22 | Popova 2021 [92] |
K102s | 19 | FLKRWARSTRWGTASCGGS | Oligomers | > 80% reduction in ThT Fluorescence at 1:1 (αS:Peptide) | 23 | Popova 2021 [92] |
p216 | 11 | WFQNRRMKWKK | Oligomers | Improved cell viability by ~ 20% in SH-SY5Y MTT Cytotoxicity assays. | 24 | Pirhaghi 2022 [93] |
PSMα3 | 22 | MEFVAKLFKFFKDLLGKFLGNN | Type B [97] oligomers Fibrils | 1. >90% reduction in ThT Fluorescence at 1:1 (αS:Peptide) 2. Kd of 3.62nM for toxic type B* oligomers | 25 | Santos 2021 [79] |
LL-37 | 37 | LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES | Type B [97] oligomers Fibrils | 1. >80% reduction in ThT Fluorescence at 2:1 (αS:Peptide) 2. Kd of 5.14nM for toxic type B* oligomers | 26 | Santos 2021 [79] |
CP1 | 8 | CPWCSTRV | Unknown | Reduced neurodegeneration in C.elegans by 74% | 27 | Kritzer 2009 [86] |
CP2 | 8 | CALCDPWW | Unknown | Reduced neurodegeneration in C.elegans by 74% | 28 | Kritzer 2009 [86] |
BD1 | 16 | DYSGLIKWTTALLRTYC(DY = N-chloroacetyl-D-tyrosine, which cyclises with downstream cys to form a thioether-macrocycle) | Unknown | > 95% reduction in ThT Fluorescence at 1:1 (αS:Peptide) | 29 | Ikenoue 2023 [95] |