Table 1.

The Structure–Activity Relationship of TTR Amyloidogenesis Inhibitors

Category	Compounds	SAR	References
T4	T4	Key interacting residues Glu54, Lys15, Leu17, Ala108, Thr119, Leu110, Ser117 in the binding sites; occupies halogen-binding pockets P1, P2, and P3.	[16]
Bisaryl structures with a linker	Bisaryl structures	Thyroid hormone-like substitution (3,5-X-4-OH, where X=CH3, F, Cl, Br, and I) produces potency; The linker Y designed as non-polar E-olefin or –CH2CH2- group also generates high selection.	[22]
		Position 2.6; 2.5; 2; 3,4,5 and 3.5 substitutions generate excellent potency and selectivity, and the efficacy scores are 0.789, 0.748, 0.734, 0.697 and 0.538, respectively.	[24]
	Diflunisal	Reaches the maximal therapeutic concentration of 224 μM in vitro, leading to 0.85 eq of drug bound to TTR.	[26]
	Flurbiprofen	Flank on both sides by the hydrophobic side chains of Lys15, Leu17, Ala108, Leu110, Ser117, Thr119, and Val121; The substituted phenyl ring forms interacts with Val17 and Ala108. CH3CHCOOH substituent interacts with Lys15.	[27]
	Bromodiflunisal	The binding potencies with values of 0.85 and 0.53, respectively, calculated by EC50 T4/EC50 tested compound, compared with that of T4 (the value of 1).	[29]
	Iododiflunisal	Interacts with Leu17, Thr106, Ala108, Thr119, and Val121. The value of EC50 (T4)/EC50 (I) is 0.7, compared with that of T4 (the value of 1).	[30]
	PCBs, OH-PCBs	Bind to TTR tetramer with Ki values of 10–140 nM, similar to the natural ligand T4 (a Ki value of 62 nM)	[37]
	LC-PCB sulfates	Produces hydrogen bonding between the sulfate groups and Lys15. Binds to TTR with equilibrium dissociation constants in the range of 4.8–16.8 nM, similar to that for T4 with 4.7 nM.	[46]
Flavonoids	Flavonoid	The more hydroxyl groups, the lower the conversion degree to amyloid fibrils.	[60]
	Apigenin	Exhibits the conversion value of 6% at the concentration of 10.8 μM and completely inhibiting fibril formation at 36 μM. Inhibits TTR disaggregation with an IC50 value of 10.3 μM, compared with T4 with IC50 value of 4.34 μM.	[60]
	Luteolin	In V30M TTR, Lut inhibits TTR disaggregation with an IC50 value of 5.68 ± 1.10 μM, compared with that in the wild type of TTR with an IC50 value of 6.38 ± 1.17 μM,	[63,64]
β-amin-oxypropionic acids	Compounds 283–299	Different from T4, the aromatic ring is mainly docked into P3 and interacts with the residues near Ser117 and Lys15 and plays a role in deciding the binding mode.	[68]
Crown Ethers	Compounds 315	Inhibit the formation of TTR-related amyloid fibril by 58% (at a concentration of 2 mM). Different from T4 in inhibiting mechanism, Compounds 315 located on the surface of TTR to stabilize the tetramer.	[70]
	Compounds 317	Inhibit the formation of TTR-related amyloid fibril by 47% (at a concentration of 10 mM). Different from T4 in inhibiting mechanism, Compounds 317 located on the surface of TTR to stabilize the tetramer.	[15]
Oxazoles	Compounds 327	A carboxyl group at C-4 demonstrates efficiency in inhibiting TTR amyloidogenesis. Substitution of ethyl, propyl, or CF3 group at C-5 enhances the inhibiting activity.	[77]
γ-Mangostin	γ-Mangostin	Inhibit the amyloid fibril formation of V30M amyloidogenic TTR with EC50 value of 7 ± 0.6 μM. X-ray crystallographic analysis reveals a novel diagonal model for binding to T4- binding sites, associating with two chloride ions.	[78]
Quinoline	Compound 329	Inhibits TTR fibril formation with an IC50 value of 1.49 μM against wild-type TTR and 1.63 μM against V30M TTR variant. Exhibit 80% inhibition against more amyloidogenic V30M-TTR at a concentration equal to the V30M-TTR tetramer over a 120 h time course.	[79]