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Orders Norzivirales and Timlovirales
Published in Paul Pumpens, Peter Pushko, Philippe Le Mercier, Virus-Like Particles, 2022
Paul Pumpens, Peter Pushko, Philippe Le Mercier
The x-ray crystallography led to a real breakthrough in understanding the protein-RNA interactions that were occurring during the RNA phage translational repression and genome encapsidation. Thus, the first crystal structure of a complex of recombinant MS2 capsids with the 19-nucleotide RNA operator was resolved at 2.7 Å (Valegård et al. 1994b, 1997; Stockley et al. 1995). Then, the crystal structures of the MS2 VLPs complexed with the RNA aptamers, which differed by their secondary structure from wild-type RNA (Convery et al. 1998; Rowsell et al. 1998; Grahn et al. 1999) or involved the presence of 2′-deoxy-2-aminopurine at the critical -10 position of the operator (Horn et al. 2004) were resolved. Further, the structure of the coat protein complexed with the operator RNA fragments were also solved by x-ray crystallography for the phages PP7 (Chao et al. 2008), PRR1 (Persson et al. 2013), and Qβ (Rumnieks and Tars 2014). Although the overall binding mode of the stem-loop to the coat was similar in all the studied cases, the details were surprisingly different among different phages. However, it should be noted here that all attempts to identify analogous coat-RNA interactions in the acinetophage AP205 and caulophage φCb5 failed until now (Kaspars Tārs, unpublished observations), suggesting that mechanisms of genome recognition and translational repression might differ significantly among the distant levivirus members. Figure 25.8 compares the different binding modes of the coat dimer-operator complexes of the phages MS2, Qβ, and PP7.
The Emerging Field of RNA Nanotechnology
Published in Lajos P. Balogh, Nano-Enabled Medical Applications, 2020
Typically, RNA contains a large variety of single-stranded stem-loops for intra- and/or inter-molecular interactions. These loops can serve as mounting dovetails, and thus external linking dowels might not be needed for nanomachine fabrication and assembly. Loops and motifs also allow for construction of a more complicated secondary structure. Versatility and low-energy folding delivers a significant advantage. Furthermore, RNA molecules can possess special functionalities such as aptamer, riboswitch, ribozyme, and siRNA.
3D Particles
Published in Paul Pumpens, Single-Stranded RNA Phages, 2020
Bleckley and Schroeder (2012) turned to the structure of the RNA stem-loop. Since the RNA hairpin motif appeared as energetically unfavorable and the free energy predictions were biased against this motif, the authors used computer programs called Crumple, Sliding Windows, and Assembly to predict the viral RNA secondary structures when the traditional assumptions of the RNA structure prediction by free energy minimization might not apply. These methods allowed incorporation of global features of the RNA fold and motifs that were difficult to include directly in minimum free energy predictions. For example, for the MS2 RNA, the experimental data from SELEX experiments, crystallography, and theoretical calculations of the path for the series of hairpins were incorporated into the RNA structure prediction, and thus the influence of the free energy considerations was modulated. This approach thoroughly explored conformational space and generated an ensemble of secondary structures (Bleckley and Schroeder 2012).
Challenges with the discovery of RNA-based therapeutics for flaviviruses
Published in Expert Opinion on Drug Discovery, 2023
Mei-Yue Wang, Rong Zhao, Yu-Lan Wang, De-Ping Wang, Ji-Min Cao
Recent studies have revealed the structures that are critical for the replication of flaviviruses and may provide insights into the design of antiviral drugs to fight against flaviviruses. For example, at the 5’ end of the RNA genome of flaviviruses, there is a ~ 70 nucleotide stem-loop structure called stem-loop A (SLA), which promotes RNA synthesis. The non-structural protein 5 (NS5) of the flavivirus specifically recognizes SLA to activate the synthesis of RNA and the methylation of the 5’ guanosine cap [150]. Another study showed that the endoplasmic reticulum-localized RNA-binding proteins (RBPs), ribosome-binding protein 1 (RRBP1), and vigilin, can directly bind to viral RNA and play a role in the distinct stages of the life cycle of flaviviruses, providing an RNA-centric perspective on the viral infection [151]. It can be inferred that RNA-based candidates that target SLA, RRBP1, and vigilin may interfere with the life cycle of flaviviruses and therefore have the potential to function as antivirals.
Discovery of RNA-targeted small molecules through the merging of experimental and computational technologies
Published in Expert Opinion on Drug Discovery, 2023
A second area that requires improvement is the way we approach screening. With our predilection for drug-like small molecules, we tend to screen against RNA molecules with complex structures. There is a danger to this – we may preclude opportunities to discover drugs for diseases linked to RNAs with simpler structures. Repeat sequences that form stem loop structures are a good case in point. While we should continue our pursuit of drug-like modulators of RNA, we should in parallel venture outside the Lipinski space by screening with more diverse chemical libraries. Along with trying different chemical space, should resources allow, it would be beneficial to screen against a variety of RNA motifs using one chemical library, a strategy previously employed with 2DCS [124] and DEL screening [104]. This not only helps in weeding out promiscuous RNA binders but also in the comprehensive characterization of compound libraries.
COVID-19: a wreak havoc across the globe
Published in Archives of Physiology and Biochemistry, 2023
Heena Rehman, Md Iftekhar Ahmad
The genome of coronavirus is positive-sense, non-segmented, linear RNA of 28–32 kilobase (Lee et al. 1991, Bonilla et al.1994, Drosten et al. 2003). The genome is helically coiled and is encapsulated by nucleocapsid (N) protein. The genome consists of 5′ cap structure and 3′ poly adenine (A) tail which facilitates in acting as mRNA for translation of polyproteins (Van Marle et al. 1995). The replicase gene comprises around 20 kilobase of the genome and encodes non-structural proteins. The 5′ end of RNA consists of leader sequence and untranslated region that contains multiple stem-loop structure. This multiple stem lop structure is required for replication and transcription. The 3′ (untranslated region) UTR is essential for the replication and synthesis of viral RNA. The gene in coronavirus is organised as 5′leader-UTR-replicase-S-E-M-N-3’UTR-poly(A) tail (Figure 2). The accessory proteins are not important for in vitro replication, but they play a significant role in the pathogenesis (Zhao et al. 2012).