A new hope for curing the common cold, a new type of NMT inhibitor
May 17, 2018 Source: CPhI Pharma Online Author: drizzly rain
Window._bd_share_config={ "common":{ "bdSnsKey":{ },"bdText":"","bdMini":"2","bdMiniList":false,"bdPic":"","bdStyle":" 0","bdSize":"16"},"share":{ }};with(document)0[(getElementsByTagName('head')[0]||body).appendChild(createElement('script')) .src='http://bdimg.share.baidu.com/static/api/js/share.js?v=89860593.js?cdnversion='+~(-new Date()/36e5)];The novel molecule IMP-1088 (yellow part of the figure) blocks human N-myristoyltransferase (NMT) (blue in the figure).
[Source: Imperial College London]
Researchers have developed a new class of drug molecules that can completely block the replication of the virus that causes the common cold by preventing the virus from invading human cells. Laboratory tests have shown that new molecules can block the replication of many viruses in cells and are effective against many other viruses in the same picornavirus family, including polioviruses and viruses that cause foot-and-mouth disease.
A team led by Dr. Edward Tate, Department of Chemistry, Imperial College London, UK, published their latest research in an article entitled "Fragment-Derived Inhibitors of Human N-Myristoyltransferase Block Capsid Assembly and Replication of the Common Cold Virus" by Nature Chemistry. progress. They hope to complete preclinical testing of new compounds before entering clinical trials.
The common cold has caused inconvenience to most of us, but it can cause serious complications in patients with asthma and chronic obstructive pulmonary disease (COPD). If you take such a drug early in the infection, you may benefit a lot, and the team is currently developing an inhaler to get the drug into the lungs quickly.
The most common cause of a cold is rhinovirus, and many people with colds experience relatively mild symptoms, which may include runny nose, sore throat, and mild fever. Rhinovirus infection can cause serious complications in patients with existing respiratory diseases such as asthma, COPD and cystic fibrosis. Rhinoviruses are members of the picornavirus family, including pathogens such as poliovirus, foot-and-mouth disease virus, coxsackie virus, hepatitis A virus, and enterovirus 71.
The current common cold treatment can only help relieve symptoms, not prevent or treat viral infections. Part of the reason for this is that there are more than 100 different rhinovirus variants that make no effective broad-spectrum vaccine, and part of the reason that the virus can rapidly mutate to produce resistance to targeted drugs.
The assembly of the rhinovirus capsid relies on the activity of an enzyme in the human body, namely N-myristoyltransferase (NMT), which modifies a capsid protein VP0 of the virus by the process of myristoylation. Human NMT exists in two forms, NMT1 and NMT2. Previous studies of poliovirus have shown that NMT is a prerequisite for capsid replication and infection. Therefore, NMT is an attractive antiviral drug target with minimal propensity for viral variation and is almost a constant factor in viral replication.
Although Imperial College researchers and other research groups have previously synthesized NMT inhibitors, to date, these molecules have been directed primarily at NMT in protozoan parasites or fungi, and they have only partially reduced the activity of the enzyme. A range of molecules optimized for human NMT can greatly improve cell viability and can be used to explore the potential of anti-hepatitis virus to inhibit NMT.
The researchers conducted high-throughput compound screening to identify compounds that have some activity on human NMT1 (HsNMT1) as a starting point for the development of effective molecules that inhibit the human HsNMT1/2 enzyme. The design process utilized fragment reconstruction methods by which the researchers constructed fragment compounds with "significant synergistic inhibitory effects and complementary binding patterns" and then linked them together to produce the most potent human NMT inhibitor, named IMP. -1088. The following figure shows the structure of the compounds of IMP-1088 and IMP-1031, and their IC50 data for inhibition of HsNMT1 and HsNMT2 in vitro.
Initial studies confirmed that IMP-1088 blocked the assembly of the rhinovirus capsid in human cells. NMT inhibitors using IMP-1088 and similar compounds can also block the production of infectious picornaviruses in human cells and protect cells from virus-induced cytotoxicity. Encouragingly, IMP-1088 exhibited strong antiviral effects against a range of rhinovirus types as well as against picornaviruses PV and FMDV.
IMP-1088 also blocks viral replication in human bronchial epithelial cells, and the effect of IMP-1088 is maintained even during the combined administration of the inhaled corticosteroid fluticasone propionate (for the treatment of patients with COPD and asthma). After the withdrawal of IMP-1088, NMT activity recovered rapidly and had no long-term effects on cell viability.
It is worth noting that IMP-1088 significantly inhibited the production of infectious virus even after taking it 3 hours after infection, indicating that the compound remains effective in the face of active infection.
However, the compound also requires a number of toxicological studies to determine whether the benefits of the efficacy and novel mechanism of action outweigh the potential risks. This drug intervention therapy also needs to be diagnosed as soon as possible after infection with a cold virus, but there is no suitable diagnostic method.
In any case, the human NMT target deserves further study as a drug target for myristoylation-dependent picornavirus infection in the treatment of RV-induced asthma, COPD, cystic fibrosis and other small RNA lesions. There are potential applications.
references:
1.Common Cold Blocked from Replicating by Novel Drug Molecule
2. Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus
3. Common cold cure on horizon after new drug successfully kills multiple strains of the virus
4. Molecule compared acts on human patients might serve for 'irresistible' cold cure
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