Abstract:The pandemic caused by the novel betacoronavirus SARS-CoV-2 has already claimed more than 3.5 million lives. Despite the development and use of anti-COVID-19 vaccines, the disease remains a major public health challenge throughout the world. Large-scale screening of the drugs already approved for the treatment of other viral, bacterial, and parasitic infections, as well as autoimmune, oncological, and other diseases is currently underway as part of their repurposing for development of effective therapeutic age… Show more
“…Initially designed as molecular probes for studying RNA/DNA-recognizing enzymes, fleximers have shown significant promise in antiviral research, including the development of coronavirus inhibitors [ 27 ]. Among the available fleximers, we selected the ATP mimetic Flex-nt10 (analog of 8-aza-7-deazaadenosine 5'-triphosphate), the adenosine mimetics Flex-ns10 (8-aza-7-deazaadenosine analog) and Flex-ns12 (8-aza-3,7-dideazaadenosine analog), and the deoxyadenosine mimetic Flex-dns12 [ 28 , 29 ].…”
Section: Resultsmentioning
confidence: 99%
“…In addition to purine nucleoside derivatives, we considered a well-known cytidine analog NHC (β-D-N 4 -hydroxycytidine, Figure 4 a) [ 30 ] and several recently reported pyrimidine derivatives ( Figure 4 c,d) that inhibited SARS-CoV-2 in vitro. These derivatives included 5′-norcarbocyclic (NorC) analogs of 3H-pirrolo[2,3-d]-pyrimidine-2-one (NorC-24p) and 3H-furano[2,3-d]-pyrimidine-2-one (NorC-24f) nucleosides with a hydrophobic 4-pentylphenyl substituent ( Figure 4 c) [ 29 ] and perylene-harboring uridine analogs Peryl-8 and Peryl-5 (neutral and positively charged derivatives, respectively, Figure 4 d) [ 31 ]. To verify the importance of charged and hydrophobic fragments, we also tested the non-nucleoside neutral perylene derivatives Peryl-2a and Peryl-2b, their positively charged analogs Peryl-3a and Peryl-3b, and an additional positively charged compound with in vivo-confirmed antiviral activity Peryl-10 ( Figure 4 d) [ 31 ].…”
Section: Resultsmentioning
confidence: 99%
“…To verify the importance of charged and hydrophobic fragments, we also tested the non-nucleoside neutral perylene derivatives Peryl-2a and Peryl-2b, their positively charged analogs Peryl-3a and Peryl-3b, and an additional positively charged compound with in vivo-confirmed antiviral activity Peryl-10 ( Figure 4 d) [ 31 ]. The codes of all small molecules were taken from the previous works [ 29 , 31 ] and the prefixes indicate small molecule types.…”
Section: Resultsmentioning
confidence: 99%
“… Code Effects on the N-RNA Condensates a Antiviral Activity, IC50 ± SD, µM b S/S control ± SD Count/Count control ± SD ATP 0.4 ± 0.1 0.5 ± 0.2 - NHC 0.5 ± 0.3 0.4 ± 0.1 8 ± 5, refs. [ 29 , 31 ] c NorC-24p 11 ± 1 6.2 ± 0.8 21 ± 6, ref. [ 29 ] c NorC-24f 15 ± 1 9 ± 2 ≥50 c Flex-nt10 b 2 ± 1 4.7 ± 0.3 - Flex-ns10 2.9 ± 0.9 2.4 ± 0.4 >100 c Flex-ns12 0.4 ± 0.1 0.4 ± 0.1 >100 c Flex-dns12 3 ± 1 4 ± 1 >100 c Peryl-8 23 ± 7 1.4 ± 0.4 1.3 ± 0.4, ref.…”
The life cycle of severe acute respiratory syndrome coronavirus 2 includes several steps that are supposedly mediated by liquid–liquid phase separation (LLPS) of the viral nucleocapsid protein (N) and genomic RNA. To facilitate the rational design of LLPS-targeting therapeutics, we modeled N-RNA biomolecular condensates in vitro and analyzed their sensitivity to several small-molecule antivirals. The model condensates were obtained and visualized under physiological conditions using an optimized RNA sequence enriched with N-binding motifs. The antivirals were selected based on their presumed ability to compete with RNA for specific N sites or interfere with non-specific pi–pi/cation–pi interactions. The set of antivirals included fleximers, 5′-norcarbocyclic nucleoside analogs, and perylene-harboring nucleoside analogs as well as non-nucleoside amphiphilic and hydrophobic perylene derivatives. Most of these antivirals enhanced the formation of N-RNA condensates. Hydrophobic perylene derivatives and 5′-norcarbocyclic derivatives caused up to 50-fold and 15-fold enhancement, respectively. Molecular modeling data argue that hydrophobic compounds do not hamper specific N-RNA interactions and may promote non-specific ones. These findings shed light on the determinants of potent small-molecule modulators of viral LLPS.
“…Initially designed as molecular probes for studying RNA/DNA-recognizing enzymes, fleximers have shown significant promise in antiviral research, including the development of coronavirus inhibitors [ 27 ]. Among the available fleximers, we selected the ATP mimetic Flex-nt10 (analog of 8-aza-7-deazaadenosine 5'-triphosphate), the adenosine mimetics Flex-ns10 (8-aza-7-deazaadenosine analog) and Flex-ns12 (8-aza-3,7-dideazaadenosine analog), and the deoxyadenosine mimetic Flex-dns12 [ 28 , 29 ].…”
Section: Resultsmentioning
confidence: 99%
“…In addition to purine nucleoside derivatives, we considered a well-known cytidine analog NHC (β-D-N 4 -hydroxycytidine, Figure 4 a) [ 30 ] and several recently reported pyrimidine derivatives ( Figure 4 c,d) that inhibited SARS-CoV-2 in vitro. These derivatives included 5′-norcarbocyclic (NorC) analogs of 3H-pirrolo[2,3-d]-pyrimidine-2-one (NorC-24p) and 3H-furano[2,3-d]-pyrimidine-2-one (NorC-24f) nucleosides with a hydrophobic 4-pentylphenyl substituent ( Figure 4 c) [ 29 ] and perylene-harboring uridine analogs Peryl-8 and Peryl-5 (neutral and positively charged derivatives, respectively, Figure 4 d) [ 31 ]. To verify the importance of charged and hydrophobic fragments, we also tested the non-nucleoside neutral perylene derivatives Peryl-2a and Peryl-2b, their positively charged analogs Peryl-3a and Peryl-3b, and an additional positively charged compound with in vivo-confirmed antiviral activity Peryl-10 ( Figure 4 d) [ 31 ].…”
Section: Resultsmentioning
confidence: 99%
“…To verify the importance of charged and hydrophobic fragments, we also tested the non-nucleoside neutral perylene derivatives Peryl-2a and Peryl-2b, their positively charged analogs Peryl-3a and Peryl-3b, and an additional positively charged compound with in vivo-confirmed antiviral activity Peryl-10 ( Figure 4 d) [ 31 ]. The codes of all small molecules were taken from the previous works [ 29 , 31 ] and the prefixes indicate small molecule types.…”
Section: Resultsmentioning
confidence: 99%
“… Code Effects on the N-RNA Condensates a Antiviral Activity, IC50 ± SD, µM b S/S control ± SD Count/Count control ± SD ATP 0.4 ± 0.1 0.5 ± 0.2 - NHC 0.5 ± 0.3 0.4 ± 0.1 8 ± 5, refs. [ 29 , 31 ] c NorC-24p 11 ± 1 6.2 ± 0.8 21 ± 6, ref. [ 29 ] c NorC-24f 15 ± 1 9 ± 2 ≥50 c Flex-nt10 b 2 ± 1 4.7 ± 0.3 - Flex-ns10 2.9 ± 0.9 2.4 ± 0.4 >100 c Flex-ns12 0.4 ± 0.1 0.4 ± 0.1 >100 c Flex-dns12 3 ± 1 4 ± 1 >100 c Peryl-8 23 ± 7 1.4 ± 0.4 1.3 ± 0.4, ref.…”
The life cycle of severe acute respiratory syndrome coronavirus 2 includes several steps that are supposedly mediated by liquid–liquid phase separation (LLPS) of the viral nucleocapsid protein (N) and genomic RNA. To facilitate the rational design of LLPS-targeting therapeutics, we modeled N-RNA biomolecular condensates in vitro and analyzed their sensitivity to several small-molecule antivirals. The model condensates were obtained and visualized under physiological conditions using an optimized RNA sequence enriched with N-binding motifs. The antivirals were selected based on their presumed ability to compete with RNA for specific N sites or interfere with non-specific pi–pi/cation–pi interactions. The set of antivirals included fleximers, 5′-norcarbocyclic nucleoside analogs, and perylene-harboring nucleoside analogs as well as non-nucleoside amphiphilic and hydrophobic perylene derivatives. Most of these antivirals enhanced the formation of N-RNA condensates. Hydrophobic perylene derivatives and 5′-norcarbocyclic derivatives caused up to 50-fold and 15-fold enhancement, respectively. Molecular modeling data argue that hydrophobic compounds do not hamper specific N-RNA interactions and may promote non-specific ones. These findings shed light on the determinants of potent small-molecule modulators of viral LLPS.
“…As a result, the nitrogenous base retains the necessary hydrogen bonds and aromatic properties that are required for recognition, while gaining the flexibility to adapt to the enzyme binding site and potential mutations. It has been shown that such compounds are able to inhibit the replication of HCoV-NL63 and MERS-CoV coronaviruses in cell culture [ 11 , 12 ]. The idea of fleximer compounds was developed further in the form of the synthesis of “reverse” fleximers ( Fig.…”
The development of specific drugs against SARS-CoV-2 infection is a major challenge facing global science and healthcare. Despite numerous attempts, there are still no truly effective drugs. Currently, the main approach in the creation of drugs against COVID-19 is repurposing, i.e., re-profiling existing drugs approved for medical use, for example, the use of a drug for the treatment of Ebola—Remdesivir, and the use of a drug for the treatment of influenza—Favipiravir. However, it is already obvious that these drugs are not specific enough nor effective enough. Another promising approach is the creation of new molecules, but it should be noted immediately that implementation requires much more time and costs. However, the search for new SARS-CoV-2 specific antiviral agents continues. The aim of our work was the creation of new 5-substituted uridine derivatives as potential inhibitors of coronavirus RNA-dependent RNA polymerase. The substances were obtained in high yields by the Suzuki‒Miyaura reaction and characterized using modern physicochemical methods. However, testing of their antiviral activity against SARS-CoV-2 did not reveal a significant inhibitory effect.
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