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▎WuXi AppTec Content Team Editor According to the latest statistics from Johns Hopkins University, the total number of cumulative new crown cases in the world has approached 400 million, and the total number of new crown disease deaths has exceeded 5.
7 million
.
Although a variety of new crown vaccines have come out, in the face of the emerging new crown variants, we still need more new control methods in case of emergency
.
Today, the top academic journal "Nature" published a new paper on anti-coronavirus drugs in the form of accelerated preview
.
The researchers screened about 18,000 different drugs and found some potential treatments with antiviral activity, some of which have been approved by regulators for Covid-19, underscoring the reliability of their screening methods
.
The study also discovered a new type of therapy, which is expected to have a synergistic effect when used in combination with existing antiviral drugs to better treat the new crown disease
.
This also has implications for future clinical development
.
In the paper, the scientists pointed out that RNA viruses such as the new coronavirus use an enzyme called RNA-dependent RNA polymerase (RdRp) to replicate RNA, and a class of drugs called nucleoside analogs can interfere with this step, making The process of viral RNA replication is terminated, or a mutation occurs, which ultimately inhibits viral replication
.
In other disease areas, many nucleoside analogs have been approved
.
Considering that the structure of RdRp is relatively conserved in different viruses, some existing nucleoside analogs may also have inhibitory effects on 2019-nCoV
.
Image source: WuXi AppTec Content team mapping To quickly find these potential drugs, scientists used human respiratory tract cells to screen small-molecule compound libraries
.
The compound library contains about 18,000 drugs that have been approved as well as drugs that are in clinical development or known to have antiviral activity
.
The researchers treated human airway cells with the drugs before infecting them with the new coronavirus
.
After 48 hours, they went to quantitatively assess the severity of the infection
.
After comprehensively evaluating the inhibitory ability and toxicity of the new coronavirus, the researchers found 122 different compound molecules
.
They belong to different types, of which about 13% are nucleoside analogs
.
Among them, the researchers discovered remdesivir and molnupiravir, which are two anti-coronavirus therapies that have been approved by multiple regulatory agencies around the world, and also verified the reliability of their screening system from the side
.
▲ The nucleoside analogs screened in this study (image source: Reference [1]) It is worth mentioning that nucleoside analogs can not only affect the replication of DNA or RNA by mimicking nucleosides, but also affect the inhibition of nucleoside Enzymes required for synthesis, thereby inhibiting nucleoside synthesis
.
Among the nucleoside analogs found in this large-scale screening, some have the function of inhibiting nucleoside synthesis
.
These molecules are not toxic to the cells used at concentrations capable of exerting antiviral efficacy
.
In addition, different molecules are also cell-specific, for example, a molecule called tubercidin has antiviral activity in Calu-3 (the cell line used in this study), Caco-2 and Huh7.
5 cell lines, while a molecule called Thioguanine and Molecules of 6-Mercaptopurine are active in Calu-3 and A549-Ace2 cell lines
.
This finding has important implications, because the same nucleoside analogs may exert a synergistic effect of "one plus one is greater than two" if the pathways of action are different
.
In this study, the scientists also screened and found three molecules: DHODH inhibitor BAY-2402234 and Brequinar, and UMPS inhibitor pyrazofurin
.
They are all capable of inhibiting pyrimidine biosynthesis with low toxicity in the cell lines used
.
In addition, they also confirmed that the function of these three molecules is only to inhibit pyrimidine synthesis, because if additional cytosine and/or uracil are provided, these molecules lose their effect of inhibiting the new coronavirus
.
▲The combination of two nucleoside analogs with different mechanisms can play the role of "one plus one is greater than two" (Image source: Reference [1]) Subsequently, researchers found two DHODH inhibitors with remdesivir or The combination of molnupiravir can play an "amazing" synergistic effect
.
Similarly, the combination of pyrazofurin and remdesivir or molnupiravir can also have a synergistic effect
.
On the contrary, if remdesivir is only used in combination with molnupiravir, it is only a simple accumulation of effects, and "one plus one is greater than two" is not achieved
.
For different new coronavirus variants (alpha, beta, gamma, delta), the researchers confirmed that these antiviral treatments are effective
.
Although the mechanism behind it is unknown, the researchers pointed out that the new coronavirus can be inhibited more effectively if pyrimidine synthesis is inhibited
.
This may also inspire new drug development ideas in the future, which is expected to bring new treatments to the clinic
.
Reference: [1] Schultz, DC, Johnson, RM, Ayyanathan, K.
et al.
Pyrimidine inhibitors synergize with nucleoside analogues to block SARS-CoV-2.
Nature (2022).
https://doi.
org/10.
1038/ s41586-022-04482-x
7 million
.
Although a variety of new crown vaccines have come out, in the face of the emerging new crown variants, we still need more new control methods in case of emergency
.
Today, the top academic journal "Nature" published a new paper on anti-coronavirus drugs in the form of accelerated preview
.
The researchers screened about 18,000 different drugs and found some potential treatments with antiviral activity, some of which have been approved by regulators for Covid-19, underscoring the reliability of their screening methods
.
The study also discovered a new type of therapy, which is expected to have a synergistic effect when used in combination with existing antiviral drugs to better treat the new crown disease
.
This also has implications for future clinical development
.
In the paper, the scientists pointed out that RNA viruses such as the new coronavirus use an enzyme called RNA-dependent RNA polymerase (RdRp) to replicate RNA, and a class of drugs called nucleoside analogs can interfere with this step, making The process of viral RNA replication is terminated, or a mutation occurs, which ultimately inhibits viral replication
.
In other disease areas, many nucleoside analogs have been approved
.
Considering that the structure of RdRp is relatively conserved in different viruses, some existing nucleoside analogs may also have inhibitory effects on 2019-nCoV
.
Image source: WuXi AppTec Content team mapping To quickly find these potential drugs, scientists used human respiratory tract cells to screen small-molecule compound libraries
.
The compound library contains about 18,000 drugs that have been approved as well as drugs that are in clinical development or known to have antiviral activity
.
The researchers treated human airway cells with the drugs before infecting them with the new coronavirus
.
After 48 hours, they went to quantitatively assess the severity of the infection
.
After comprehensively evaluating the inhibitory ability and toxicity of the new coronavirus, the researchers found 122 different compound molecules
.
They belong to different types, of which about 13% are nucleoside analogs
.
Among them, the researchers discovered remdesivir and molnupiravir, which are two anti-coronavirus therapies that have been approved by multiple regulatory agencies around the world, and also verified the reliability of their screening system from the side
.
▲ The nucleoside analogs screened in this study (image source: Reference [1]) It is worth mentioning that nucleoside analogs can not only affect the replication of DNA or RNA by mimicking nucleosides, but also affect the inhibition of nucleoside Enzymes required for synthesis, thereby inhibiting nucleoside synthesis
.
Among the nucleoside analogs found in this large-scale screening, some have the function of inhibiting nucleoside synthesis
.
These molecules are not toxic to the cells used at concentrations capable of exerting antiviral efficacy
.
In addition, different molecules are also cell-specific, for example, a molecule called tubercidin has antiviral activity in Calu-3 (the cell line used in this study), Caco-2 and Huh7.
5 cell lines, while a molecule called Thioguanine and Molecules of 6-Mercaptopurine are active in Calu-3 and A549-Ace2 cell lines
.
This finding has important implications, because the same nucleoside analogs may exert a synergistic effect of "one plus one is greater than two" if the pathways of action are different
.
In this study, the scientists also screened and found three molecules: DHODH inhibitor BAY-2402234 and Brequinar, and UMPS inhibitor pyrazofurin
.
They are all capable of inhibiting pyrimidine biosynthesis with low toxicity in the cell lines used
.
In addition, they also confirmed that the function of these three molecules is only to inhibit pyrimidine synthesis, because if additional cytosine and/or uracil are provided, these molecules lose their effect of inhibiting the new coronavirus
.
▲The combination of two nucleoside analogs with different mechanisms can play the role of "one plus one is greater than two" (Image source: Reference [1]) Subsequently, researchers found two DHODH inhibitors with remdesivir or The combination of molnupiravir can play an "amazing" synergistic effect
.
Similarly, the combination of pyrazofurin and remdesivir or molnupiravir can also have a synergistic effect
.
On the contrary, if remdesivir is only used in combination with molnupiravir, it is only a simple accumulation of effects, and "one plus one is greater than two" is not achieved
.
For different new coronavirus variants (alpha, beta, gamma, delta), the researchers confirmed that these antiviral treatments are effective
.
Although the mechanism behind it is unknown, the researchers pointed out that the new coronavirus can be inhibited more effectively if pyrimidine synthesis is inhibited
.
This may also inspire new drug development ideas in the future, which is expected to bring new treatments to the clinic
.
Reference: [1] Schultz, DC, Johnson, RM, Ayyanathan, K.
et al.
Pyrimidine inhibitors synergize with nucleoside analogues to block SARS-CoV-2.
Nature (2022).
https://doi.
org/10.
1038/ s41586-022-04482-x
