Protein aggregation-inhibition: a therapeutic route from Parkinson’s disease to sickle cell anemia

Figures & data

Figure 1. Membrane-bound α-syn structure (2kkw.pdb) (Rao et al. 2010) showing its three regions, N-term (positively charged), the NAC (highly hydrophobic), and the C-term (negatively charged). The last amino acid of the N-term domain (Lys-60) and the first amino acid of the C-term domain (Lys-96), encompassing the NAC, are shown as vdW spheres. The chain colors correspond to the following secondary structures: α-helix (orange), turn (yellow), and coil (ice blue).

Figure 2. (a) α-syn monomer extracted from the α-syn experimental (NMR spectroscopy) protofibril reported by Tuttle et al. (2016) (2n0a.pdb). (b) α-syn dimer extracted from the same experimental protofibril; cartoon representation showing a β-sheet-rich region in the NAC (amino acids 61–95) domain; some β-sheet is also visible in the N-term region. The last amino acid of the N-term domain (Lys-60) and the first amino acid of the C-term domain (Lys-96), encompassing the NAC, are shown as vdW spheres. The chain colors correspond to the following secondary structures: 3₁₀ helix (orange), β-sheet (red), turn (yellow), and coil (ice blue).

Figure 3. (a) Normal deoxygenated (T-state) hemoglobin, deoxy-HbA (2dn2.pdb) (Park et al. 2006), showing the four heme groups and the Glu-β6 amino acid in β₁ and β₂, replaced by Val-β6 in HbS; (b) sickle-cell deoxy-HbS dimer (2HBS.pdb) (Harrington et al. 1997) showing the Val-β6 (grey spheres) in 2β₂, lodged in a hydrophobic cavity in 1β₁ formed by Ala-β70, Phe-β85, and Leu-β88 (blue spheres) (Wishner et al. 1975; Dykes et al. 1979; Padlan and Love 1985a, 1985b).

Figure 4. (a) Glu-β6 (HbA) and (b) Val-β6 (HbS) interactions with every residue from adjacent HbA and HbS tetramers, respectively. The residues forming the hydrophobic pocket in HbS-1, Ala-β70, Phe-β85, and Leu-β88, are shown in orange in (b). The most important residues in the 1β₁ (blue) and Glu-β6 and Val-β6 in the 2β₂ (red) polypeptides from a MD snapshot are shown below. The potential energy, and not the electrostatic and vdW energy, are plotted in (a) and (b), respectively. Reprinted from Galamba (2019).

Figure 5. Molecular structure of several α-syn aggregation-inhibitors: dopamine, OleA, EGCG, Curcumin, SynuClean-D, and Fasudil.

Figure 6. Molecular structure of the α-syn aggregation inhibitors squalamine and trodusquemine.

Table 1. Examples of α-syn aggregation inhibition peptides.

Aggregation inhibition peptide	α-syn parent domain/target	Ref.
68GAVVT72	NAC	El-Agnaf et al. (2004)
77VTGVTAVAQKTV82	NAC	Madine et al. (2008)
72PGVTAV77	NAC	Kim et al. (2009)
45KDGIVNGVKA54	N-term	Cheruvara et al. (2015)
KISVRV	NAC	Rezaeian et al. (2017)
GQTYVLPG	N-term	Rezaeian et al. (2017)
SUMO1(15–55)^a	N-term	Liang et al. (2021)
PSMα3^b	Oligomers/fibrils	Santos et al. (2021)
K84s^c	Oligomers	Popova et al. (2021)
K102s^d	Oligomers	Popova et al. (2021)
GVLYVGS-Aib	N-term	Horsley et al. (2022)

Hydrophobic amino acids with aliphatic side chains are displayed in blue; hydrophobic amino acids with aromatic side chains are displayed in red. The second column identifies either the region of α-syn used in the peptide design and/or the believed target region/species.

^a ₁₅DKKEGEYIKLKVIGQDSSEIHFKVKMTTHLKKLKESYCQRQ₅₅.

^b MEFVAKLFKFFKDLLGKFLGNN.

^c FLVWGCLRGSAIGECVVHGGPPSRH.

^d FLKRWARSTRWGTASCGGS.

Figure 7. Molecular structure of several α-syn deoxy-HbS aggregation inhibitors: n-propyl urea, benzyl alcohol, clofibric acid, and gemfibrozil.

Figure 8. Molecular structure of several α-syn deoxy-HbS aggregation inhibitors: phenylalanine, tryptophan, alizarin, piperine, capsaicin, and cubebin molecular structures. Phenylalanine and tryptophan exhibit some aggregation inhibition activity and were used as building blocks in aggregation inhibition peptides (Dean and Schechter 1978a; Schechter et al. 1978). Alizarin (hydroxyl anthraquinone) is a bioactive compound from the plant Rubia cordifolia. Piperine, capsaicin, and cubebin have been pointed out (Ameh et al. 2012) as possible aggregation inhibitors present in Niprisan (Iyamu et al. 2002) (drug Nix-0699) a product of the extracts of four different plants.

Table 2. Set of 50 compounds, among the 106, reported by Metaferia et al. (2022) with antisickling activity (see Table 1 of Metaferia et al. 2022 for additional details).

Compound	Compound	Compound	Compound	Compound
Ammonium trichlorotellurate	Cisplatin	Curcumin	Butein	AM-103
Niferidil	Cloturin	AEG-33783	Ethacrynic acid	ODM-103
Mavatrep	EF-4040	VRT-532	TS-80	ON-09310
Manoalide	Cyclovalone	Licochalcone A	SC-1	P-7435
HR325	VML 530	NSC-150117	Tucaresol	AZD-4769
NSD-721	Peruvoside	AT-101	CBS-1114	Calcimycin
FT-11	ONO-7746	Darapladib	YM 57158	Vadadustat
Mitapivat	BMS-919373	Oxyfedrine hydrochloride	Allisartan	Metabromsalan
ARA DMAP	KUX-1151	Octenidine	Losartan potassium	IMD-0560
Pafuramidine	NT-113	WP-1066	Samixogrel	Laflunimus

Figure 9. (a) A water pentamer next to Ile-6 in an 11-mer isoleucine peptide (₁ILE₁₁) displaying a water in the C_β coordination sphere with at least four nearest water neighbors (W-4W) and a water with three or less nearest water neighbors (W-3W) because of the proximity of the solute; (b) number of water molecules in the first hydration layer (r_min ≤ 6.45 Å) of the C_β of, Ile-6 in an 11-mer isoleucine peptide (₁ILE₁₁), Ile-6 in an 11-mer serine peptide with a single (middle) isoleucine (₁SER₅-ILE-₇SER₁₁), and Ile-4 in NAC-term (₈₅AGSIAAATGFV₉₅), an 11-mer peptide comprised of the last 11 amino acids of NAC; (c) tetrahedrality of the W-4W water populations in the first hydration shell of the C_β of Ile and Ser, respectively, in isoleucine (₁ILE₁₁) and serine (₁SER₁₁) 11-mer peptides, compared with the tetrahedrality of bulk water; (d–g) water pair interaction energy distributions, P(W···W_n) for n = 1–4, for bulk water and W-4W and W-3W water populations in the first hydration shell of the C_β of Ile in isoleucine (₁ILE₁₁).

Figure 10. (a) Deoxy-HbS monomer showing the hydrophobic pocket (yellow); (b) deoxy-HbS monomer showing Val-β6 (yellow); (c) α-syn. (blue) Hydrophobic amino acids with aliphatic side chains (Ala, Ile, Leu, Met, and Val); (red) hydrophobic amino acids with aromatic side chains (Phe, Trp, Tyr); (orange) remaining amino acids; (green) Hem in deoxy-HbS.

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