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May 14, 2018

Common Cold Blocked from Replicating by Novel Drug Molecule

The novel molecule IMP-1088 (yellow) blocks human NMT (blue), a protein essential for the cold virus to assemble the geometric capsid "shell" that encloses its RNA genome (green). [Imperial College London]

  • Scientists have developed a new class of drug molecule that can completely block the virus that causes the common cold by preventing it from hijacking human cells. Laboratory tests showed that the new molecule prevents multiple strains of the cold virus from replicating in cells, and is also effective against a number of other viruses in the same picornavirus family, including poliovirus and the virus that causes foot-and-mouth disease. 

    The scientists, headed by Edward Tate, Ph.D., at the department of chemistry, Imperial College, London, report on their developments in Nature Chemistry, in a paper entitled "Fragment-Derived Inhibitors of Human N-Myristoyltransferase Block Capsid Assembly and Replication of the Common Cold Virus.” They hope to progress the new compound into preclinical in vivo testing, before moving into the clinic. 

    “The common cold is an inconvenience for most of us, but can cause serious complications in people with conditions like asthma and chronic obstructive pulmonary disease (COPD),” comments Dr. Tate. “A drug like this could be extremely beneficial if given early in infection, and we are working on making a version that could be inhaled, so that it gets to the lungs quickly."

    The common cold is most frequently caused by rhinovirus, and while many people who develop a cold experience relatively mild symptoms that may include a runny nose, sore throat, and mild fever, rhinovirus infection can cause serious complications in patients with pre-existing respiratory diseases such as asthma, COPD, and cystic fibrosis, the authors note. Rhinovirus is a member of the Picornaviridae family, which includes pathogens such as poliovirus, foot-and-mouth disease virus, coxsackievirus, hepatitis A virus, and enterovirus 71.

    Today’s treatments for the common cold can only help to alleviate symptoms, rather than prevent or treat the viral infection. This is partly because there are more than 100 different rhinovirus variants, which “precludes the generation of broad-spectrum vaccines,” and partly because the virus rapidly mutates against drugs that target it directly.

    Assembly of the rhinovirus capsid relies on the activity of a human enzyme, N-myristoyltransferase (NMT), which carries out modification of one of the viral capsid proteins, VP0, by a process known as myristoylation. Human NMT exists in two forms, NMT1 and NMT2. Prior studies in poliovirus have shown that NMT is a prerequisite for capsid replication and infectivity. “… host NMT may therefore be an attractive antiviral drug target that is minimally susceptible to both serotypic variation and the propensity of the virus to mutate, because host NMT is an invariant factor in viral replication,” the authors state.

    While the Imperial College researchers and other teams have previously generated NMT inhibitors, to date these molecules have been developed primarily against NMT in protozoan parasites or fungi, and they only “modestly” reduce activity of the human enzymes, the team notes. “We reasoned that a new series optimized specifically against the human NMTs could deliver a greatly improved cellular activity and a tool with which to explore the antirhinoviral potential of NMT inhibition.”

    An opportunity arose while the researchers were looking at potential hits from a high-throughput compound screen against NMT in a human malaria parasite. They identified a compound that had some activity against human NMT1 (HsNMT1) and used this as a starting point for the development of a more effective molecule that could inhibit both the human NMT1 and NMT2 (HsNMT1/2) enzymes. The design processes harnessed what they describe as an “unusual fragment reconstruction approach,” through which the scientists built fragment-like compounds that had “remarkable cooperative inhibitory effects and complementary binding modes,” which they then linked together to generate the most potent human NMT inhibitor, designated IMP-1088.

    Initial studies confirmed that IMP-1088 blocked rhinoviral capsid processing in human cells. NMT inhibition using IMP-1088 and its less potent analogs also blocked the production of infectious picornaviruses in human cells and protected the cells from virus-induced cytotoxicity. Encouragingly, IMP-1088 demonstrated strong antiviral effects against a range of rhinovirus serotypes, as well as against the picornaviruses PV and FMDV.

    IMP-1088 also blocked viral replication in primary human bronchial epithelial cells, which the researchers say represent a model that is more representative of human infection. The effects of IMP-1088 were sustained even during co-administration of the inhaled corticosteroid fluticasone proprionate, which is used to treat patients with COPD and asthma.  And following IMP-1088 withdrawal, NMT activity recovered rapidly, with no long-term effects on cell viability.

    “Remarkably, IMP-1088 significantly inhibited the production of infectious virus even when added up to 3 hours postinfection, which suggests that efficacy can be maintained even in the face of an active infection,” the authors state. The results also strongly indicated that the VP0 myristoylation is “essential for the production of infectious RV [rhinovirus] particles, as previously observed for PV [picornavirus].”

    In a final set of experiments, the team demonstrated that blocking NMT acted to prevent assembly of the virus particles. Interestingly, they point out, IMP-1088 didn’t block viral RNA production or translation of the rhinovirus polyprotein. “These data suggest that the key step to mediate NMT inhibitor efficacy lies between protein translation and the production of infectious virions,” they note.

    The team acknowledges that “…extensive toxicological studies are required to determine whether the benefits of efficacy and novel mode of action outweigh the potential risks of targeting the host lipidation machinery.” Dr. Tate added that, “The way the drug works means that we would need to be sure it was being used against the cold virus, and not similar conditions with different causes, to minimize the chance of toxic side effects." Pharmaclogical intervention will also need to be coupled with much faster diagnosis in the earliest hours postinfection, “methods for which are currently lacking in the clinic,” they note.

    Nevertheless, the authors conclude, “The observation that many picornaviruses have evolved to depend on host myristoylation suggests that this mode of action might circumvent the development of resistance to a drug that targets NMT because viral mutations would not influence the inhibitor potency against a host enzyme.…The data presented here suggest that human NMT merits further investigation as a drug target in myristoylation-dependent picornavirus infections, with potential applications in the treatment of RV-induced exacerbations of asthma, COPD, cystic fibrosis and other picornaviral diseases.”

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