Table 1.

Therapeutic compounds directed against the different branches of the proteostasis network (PN). Therapeutic compounds are divided based on which branch of the PN they target, including trafficking (green), folding (blue), and degradation (red). Subgroups include compounds directed against protein lipid-modifications, (co-)chaperonins, HSR, UPR, ERAD, and autophagy. * Compounds that are not yet available.

Target	Compounds *	Function	Effect on PRs	References
Protein lipid-modifications	FTase inhibitors	Inhibits the farnesylation of proteins	(Proposed) underprenylation and mislocalization of many PR proteins	[100,101]
	GGTase-I inhibitors	Inhibits the geranylgeranylation of proteins	(Proposed) underprenylation and mislocalization of many PR proteins	[102]
(Co-)chaperonins	CCT inducers *	Improves folding of transducin and possibly other PR proteins	Undetermined	[103]
	PhLP1 inducers *	Improves function of CCTs and possibly CCT-independent functions	Malformation of OS by transgenic expression of a PhLP1 dominant-negative mutant	[47,103,104]
	CCT-BBSome stabilizers *	Stabilizes BBSome formation and thereby the export of molecules from the OS	Undetermined	[105]
	Small molecule Ric8 inhibitors *	Prevents folding of disease-causing Gα	Undetermined	[106,107]
Heat shock response (HSR)	geldanamycin, tanespimycin, alvespimycin	1st generation HSP90 inhibitors	Geldanamycin not suitable for future experiments because of poor applicability and toxicity; Tanespimycin reduced mutant protein accumulation in rat RP model (R135L); prolonged treatment with alvespimycin leads to PR cell death	[108,109,110,111,112]
	luminespib, onalespib, ganetespib, HSP990	Newer generation HSP90 inhibitors	HSP990 treatment in a RP rat model (P23H) enhances visual function and delayed PR degeneration, but prolonged treatment led to visual impairment by GRK1 and PDE6 reduction; prolonged treatment with ganetespib led to PR cell death	[109,111,112]
	AAV-HSF-1	Overexpressing HSF-1 and thereby transcriptional activation of HSPs	Subretinal injection of AAV-Hsf-1 in a RP rat model (P23H) improved visual reponse	[113]
	Arimoclomol	Induces HSR and UPR, only in stressed cells	Prolonged PR survival and improved visual responses in P23H transgenic rats	[114]
Unfolded protein response (UPR)	AAV-BiP	Relieves ER stress by reducing cleaved ATF6, phosphorylated eIF2α and CHOP	Subretinal delivery of AAV5-BiP reduced PR cell death and improved visual responses in P23H transgenic rats	[115,116]
	CHOP inhibitors *	Inhibits proapoptotic transcription activity of CHOP	CHOP knockout in a trangenic mouse model of RP (T17M) led to PR cell death and strong impairment in visual function; CHOP knockout in P23H RHO mice had no effect on PR survival in young mice, but partly protected PR degeneration in older mice	[117,118,119]
	ATF4 inhibitors *	Inhibits downstream transcription activation of Chop, Ero1, and Gadd34	ATF4 knockdown in T17M RHO mice decreased retinal degeneration and improved PR survival	[120]
	GSK2606414A	Specific PERK inhibitor	Treatment with GSK2606414A in P23H RHO rats accelerated PR cell death and further impaired visual function	[121]
	Salubrinal	Inhibitor of eIF2α dephosphorylation	Treatment with salubrinal in P23H RHO rats improved PR survival	[121]
	KIRA6	Allosterically inhibits IRE1α RNase activity	Intravitreal injection of KIRA6 in P23H RHO rats increased PR survival	[122]
	Reactive electrophilic species (RES) modulators *	Modulate the effects of RES on IRE1	Undetermined	[123,124,125,126,127,128]
	Ceapins	Selective inhibitors of ATF6α	Undetermined	[129,130]
ER-associated degradation (ERAD)	Kyoto University Substances (KUSs)	Inhibits VCP’s ATPase activity, without affecting the cellular functions of VCP	Individual treatment with KUS121 and KUS187 in a rd10 mouse model preserved ONL thickness and improved visual function	[131]
	AAA+ protein derivatives *	Unfolding of misfolded proteins	Transgenic expression of PAN in Gy-/- mice increased PR survival and preserved visual function	[132]
	DUB/USP modulators	Modulating the ubiquitin cleavage from proteins, thereby modulating proteosomal degradation	Undetermined	[133,134,135]
Autophagy	Rapamycin, everolimus, temsirolimus, ridaforolimus	Inhibiting mTOR pathway by directly binding to mTORC1	Improved rod survival in P23H-3 rats	[136]
	Metformin	Activation of AMP-activated protein kinase (AMPK)	Metformin treatment protected against retinal cell death in diabetic mice, whereas it accelerated PR degeneration in P23H RHO mice	[137,138]
	Valproic acid (VPA)	Upregulates autophagy by inhibiting inositol synthesis	VPA treatment in BBS12-/- mice, P23H RHO Xenopus laevis, and a rd1 mouse model resulted in PR protection, whereas treatment in T17M RHO X. laevis, a P23H-1 rat model, and a rd10 mouse model excerbated PR degeneration	[139,140,141]