A drug screening toolkit based on the –1 ribosomal frameshifting of SARS-CoV-2

Abstract

The –1 ribosomal frameshifting is vital for the translation of the open reading frame (ORF)1b in SARS-CoV-2. The products of ORF1b participate in viral replication. Therefore, changing the frameshift frequency reduces the survival of the virus. This study aimed to successfully develop a toolkit for screening antiviral drugs. Finally, the FDA-approved drug library was screened, revealing that ivacaftor and (–)-Huperzine A worked well in changing the –1 ribosomal frameshifting of SARS-CoV-2 in vitro .

Programmed −1 Ribosomal Frameshifting in coronaviruses: A therapeutic target

“…Similarly, this agent appears to be resistant to natural variants of the SARS-CoV-2 −1 PRF stimulating pseudoknot ( Neupane et al, 2020 ). A recent screen of a bank of approved drugs identified numerous small molecules that either stimulated or inhibited SARS-CoV-2 mediated −1 PRF ( Chen et al, 2020 ). Independently, another group identified merafloxacin, a fluoroquinolone antibacterial, as a potent inhibitor of SARS-CoV-2 −1 PRF and viral replication in Vero-E6 cells, which also showed resistance to natural mutations and activity against other human betacoronaviruses ( Sun et al, 2020 ).…”

“…A. Three examples of small molecules that have been found to inhibit −1 PRF: MTDB ( Kelly et al, 2020 ), merafloxacin ( Sun et al, 2020 ), and ivacaftor ( Chen et al, 2020 ). B.…”

Restriction of SARS-CoV-2 replication by targeting programmed −1 ribosomal frameshifting

“…In addition, an interferon-induced host protein, Shiftless (SHFL), has been shown to interact with HIV-1 FSE, inhibit −1 PRF, and restrict HIV-1 replication (15), suggesting that frameshift inhibition has become part of the host antiviral response. Several compounds have recently been shown to modulate −1 PRF of SARS-CoV-2 to varying degrees (16)(17)(18), although the specificity of these compounds and their antiviral activity remain unclear.…”

Potential 3‐chymotrypsin‐like cysteine protease cleavage sites in the coronavirus polyproteins pp1a and pp1ab and their possible relevance to COVID‐19 vaccine and drug development

“…86 The occurrence of ribosomal frameshifting is required for the production of RdRp, 70 which is needed in the second phase of translation. 70 Although the signal for ribosomal frameshifting has been well studied 57,80,[87][88][89][90] and the RNA pseudoknot is designed as a target for anti-SARS agents, 91,92 regulation of the ribosomal frameshifting mechanism remains unclarified.…”