Abstract:A rapidly evolving understanding of phase separation in the biological and physical sciences has led to the redefining of virus-engineered replication compartments in many viruses with RNA genomes. Condensation of viral, host and genomic and subgenomic RNAs can take place to evade the innate immunity response and to help viral replication. Divergent viruses prompt liquid–liquid phase separation (LLPS) to invade the host cell. During HIV replication there are several steps involving LLPS. In this review, we cha… Show more
“…LEDGF/p75 also appeared to be a highly disordered protein, with only two structured domains predicted by Alphafold2: the N-Terminal conserved PWWP motif, involved in DNA binding, notably at the level of mononucleosome ( 13 ), and the previously described IN-Binding Domain (IBD) ( 32 ). Those predictions are in perfect correlation with a recent review describing proteins involved in biocondensates and impacting the HIV replication cycle ( 23 ). Figure 1 Both IN and LEDGF/p75 proteins are predicted with several intrinsically disordered regions.…”
Section: Resultssupporting
confidence: 82%
“…The understanding of numerous biological systems indeed involves dynamic macromolecular complexes, whose assembly and activity require excluded volume and/or condensed phase environments ( 18 , 21 ). Viral infection processes have been reported to rely on LLPS formed by either viral components or cellular cofactors (Reviewed in ( 22 , 23 , 24 , 25 )). In the context of HIV infection, the HIV genome has been detected in nuclear MLOs (Membrane Less Organelles; equivalent of “in cell” LLPS) colocalizing with CPSF6, a partner of the p24 Capsid protein, targeting the integration in the dense regions of chromatin ( 26 , 27 ).…”
“…LEDGF/p75 also appeared to be a highly disordered protein, with only two structured domains predicted by Alphafold2: the N-Terminal conserved PWWP motif, involved in DNA binding, notably at the level of mononucleosome ( 13 ), and the previously described IN-Binding Domain (IBD) ( 32 ). Those predictions are in perfect correlation with a recent review describing proteins involved in biocondensates and impacting the HIV replication cycle ( 23 ). Figure 1 Both IN and LEDGF/p75 proteins are predicted with several intrinsically disordered regions.…”
Section: Resultssupporting
confidence: 82%
“…The understanding of numerous biological systems indeed involves dynamic macromolecular complexes, whose assembly and activity require excluded volume and/or condensed phase environments ( 18 , 21 ). Viral infection processes have been reported to rely on LLPS formed by either viral components or cellular cofactors (Reviewed in ( 22 , 23 , 24 , 25 )). In the context of HIV infection, the HIV genome has been detected in nuclear MLOs (Membrane Less Organelles; equivalent of “in cell” LLPS) colocalizing with CPSF6, a partner of the p24 Capsid protein, targeting the integration in the dense regions of chromatin ( 26 , 27 ).…”
“…DNA damage foci, promyelocytic leukemia nuclear bodies (PML nuclear bodies), Cajal bodies, processing bodies (P-bodies), and stress granules are prominent examples of host cell biocondensates. Viruses also utilize LLPS to ensure viral genome replication and assembly, as was demonstrated for a number of viruses, including SARS-CoV-2 and HIV-1 [29,30,32,33]. Furthermore, viruses can evade antiviral immune response through LLPS regulation and biocondensate formation [29].…”
Emerging and re-emerging viruses periodically cause outbreaks and epidemics around the world, which ultimately lead to global events such as the COVID-19 pandemic. Thus, the urgent need for new antiviral drugs is obvious. Over more than a century of antiviral development, nucleoside analogs have proven to be promising agents against diversified DNA and RNA viruses. Here, we present the synthesis and evaluation of the antiviral activity of nucleoside analogs and their deglycosylated derivatives based on a hydroxybenzo[4,5]imidazo[1,2-c]pyrimidin-1(2H)-one scaffold. The antiviral activity was evaluated against a panel of structurally and phylogenetically diverse RNA and DNA viruses. The leader compound showed micromolar activity against representatives of the family Coronaviridae, including SARS-CoV-2, as well as against respiratory syncytial virus in a submicromolar range without noticeable toxicity for the host cells. Surprisingly, methylation of the aromatic hydroxyl group of the leader compound resulted in micromolar activity against the varicella-zoster virus without any significant impact on cell viability. The leader compound was shown to be a weak inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase. It also inhibited biocondensate formation important for SARS-CoV-2 replication. The active compounds may be considered as a good starting point for further structure optimization and mechanistic and preclinical studies.
“…60 Collectively, viruses, as obligate intracellular pathogens, utilize the properties of BMCs for genome replication and interaction with host cell pathways. [61][62][63] The involvement of BMCs in the replication processes of the novel coronavirus that causes severe acute respiratory syndrome (SARS-CoV-2) has recently been studied. 64 The formation of BMCs by the nucleocapsid protein of the novel coronavirus is contingent on the presence of RNA.…”
Section: Molecular and Cellular Aspects Of Protein And Rna Condensationmentioning
confidence: 99%
“…These are areas where viruses and pathogens, such as ebolaviruses, are protected from the survivor's immune system, even after being eradicated from other parts of the body. The possibility that LLPS could play a role in this process, considering its known role in cellular compartmentalization 25,27,36,134,135 and in viral infection, 61,62,[136][137][138] is plausible but needs further research for validation.…”
Section: Rna Viruses: Survival Through Phase Separationmentioning
When the SARS‐CoV‐2 virus infects humans, it leads to a condition called COVID‐19 that has a wide spectrum of clinical manifestations, from no symptoms to acute respiratory distress syndrome. The virus initiates damage by attaching to the ACE‐2 protein on the surface of endothelial cells that line the blood vessels and using these cells as hosts for replication. Reactive oxygen species levels are increased during viral replication, which leads to oxidative stress. About three‐fifths (~60%) of the people who get infected with the virus eradicate it from their body after 28 days and recover their normal activity. However, a large fraction (~40%) of the people who are infected with the virus suffer from various symptoms (anosmia and/or ageusia, fatigue, cough, myalgia, cognitive impairment, insomnia, dyspnea, and tachycardia) beyond 12 weeks and are diagnosed with a syndrome called long COVID. Long‐term clinical studies in a group of people who contracted SARS‐CoV‐2 have been contrasted with a noninfected matched group of people. A subset of infected people can be distinguished by a set of cytokine markers to have persistent, low‐grade inflammation and often self‐report two or more bothersome symptoms. No medication can alleviate their symptoms efficiently. Coronavirus nucleocapsid proteins have been investigated extensively as potential drug targets due to their key roles in virus replication, among which is their ability to bind their respective genomic RNAs for incorporation into emerging virions. This review highlights basic studies of the nucleocapsid protein and its ability to undergo liquid–liquid phase separation. We hypothesize that this ability of the nucleocapsid protein for phase separation may contribute to long COVID. This hypothesis unlocks new investigation angles and could potentially open novel avenues for a better understanding of long COVID and treating this condition.
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