ORF6, a repressor of the MHC class I pathway: new molecular target for SARS-CoV-2 drug discovery?

Figures & data

Figure 1. SARS-CoV-2 infection inhibits the expression of MHC class I in human epithelial cells. a) Comparison of MHC class I expression levels between the nasal epithelial cells from negative participants and COVID-19 patients. MHC class I is suppressed by SARS-CoV-2 infection. b) Comparison of MHC class I expression in the primary human bronchial epithelial cells (HBEpC) infected by an influenza a virus mutant strain (IAVΔNS1) and SARS-CoV-2. IAVΔNS1 infection leads to the induction of MHC class I, whereas SARS-CoV-2 infection does not induce MHC class I.

Figure 2. SARS-CoV-2 escapes from the human immune system by suppressing the MHC class I pathway. a) Cytotoxic T cells recognize the nonpathogenic virus-infected cells through the interaction between TCR and viral antigen-loaded MHC class I complex (top panel). SARS-CoV-2 infected cells evade cytotoxic T cells by reducing cell surface expression of MHC class I molecules (bottom panel). b) SARS-CoV-2 ORF6 perturbs MHC class I induction by inhibiting STAT1 and NLRC5 nuclear importation. TCR: T-cell receptor, NLRC5: NLR family CARD domain containing 5, STAT1: signal transducer and activator of transcription 1, ORF6: SARS-CoV-2 open reading frame 6 protein.

Table 1. Therapeutic targets for COVID-19.

Virus protein	Full name/Function	Therapeutic strategy(ies)	Reference(s)
Mpro	SARS-CoV-2 main protease	Drugs: MG-101, Lycorine HCl, Nelfinavir mesylate, boceprevir.	[28,31]
		Drug-like small molecule inhibitors	[29]
		Herbal medicine	[32,33]
PLpro	SARS-CoV-2 papain-like protease	Drugs: Sitagliptin, Daclatasvir.	[28]
ORF1b	SARS-CoV-2 open reading frame 1b	RNAi	[34]
S, N, M, E	SARS-CoV-2 structural proteins: spike protein (S), nucleocapsid protein (N), membrane protein (M) and envelope protein (E).	RNAi	[39,40]
ORF6	SARS-CoV-2 open reading frame 6	RNAi	[48]

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