RIBOSFL · Restriction of HIV and coronavirus infections by the innate immunity protein Shiftless

Restriction of HIV and coronavirus infections by the innate immunity protein Shiftless

In the recent past, there has been an alarming increase in the emergence of novel pathogenic viruses like SARS-CoV-2, while relatively older viruses like HIV-1 remain without a cure. Additionally, rapid development of resistance to current therapeutics have led to a continuous need for new antiviral therapeutic strategies. To this end, –1 programmed ribosomal frameshifting (–1PRF) has gained attention as a new therapeutic target. What is –1PRF? Let us first go back to the central dogma of life- while DNA stores genetic information, which is transcribed to messenger RNAs (mRNAs), ribosomes ‘translate’ the information encoded in mRNAs to make chains of amino acids called proteins. A reading frame is simply the division of nucleotides into non-overlapping, consecutive triplets called codons. If the ribosome shifts forward or backward by 1 or 2 nucleotides, the amino acid sequence will radically change and will very often lead to the appearance of a premature stop codon. PRF is present across all domains of life but majority of the reported instances of PRF have been found in viruses. In the simplest terms, –1PRF is the backward movement of the ribosome by 1 nucleotide on the slippery site of an mRNA, when the ribosome is hindered by nearby mRNA secondary structures. C19orf66, also known as Shiftless (SFL) functions against a plethora of viruses by affecting viral RNA stability (in Dengue virus), formation of the viral replication organelle (in Hepatititis C virus), targeting viral proteins for degradation (in Zika virus) and inhibiting ribosomal frameshifting (in HIV-1 and many other viruses). For the project RIBOSFL, we will focus only on the frameshift inhibitory function of SFL. In the context of HIV-1, SFL is thought to bind simultaneously to the stem-loop and a non-canonical rotated state of a ribosome in the process of undergoing frameshifting on the slippery site. This leads to ribosomal stalling. SFL is then, believed to recruit release factors to the ribosome to terminate translation at the slippery site and prevent further translation in the –1 frame. Although SFL has mainly been studied as a frameshift inhibitor in the context of HIV-1 and Japanese Encephalitis Virus, SFL is also an effective frameshift inhibitor for SARS-CoV-2. Since SFL has many modes of antiviral action, it is possible that SFL can increase specificity for viral mRNAs by employing a combination of strategies.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз