Ricki Lewis, PhD
May 18, 2018
A potential new drug to treat the common cold prevents rhinoviruses and other picornaviruses from gaining a toehold in human cells, according to findings published in Nature Chemistry.
Aurélie Mousnier, PhD, from Imperial College London and Queen's University in Belfast, United Kingdom, and colleagues have created a "broad-spectrum antipicornaviral drug." Knowing from previous work that the viruses use a human enzyme, N-myristoyltransferases 1 and 2 (NMT), to make their protein coat, the investigators developed a small molecule inhibitor of NMT.
Targeting the human protein rather than blocking the virus directly gets around two key problems: viral diversity, which stifles vaccine efforts, and high mutation rate, which promotes evolution of drug resistance.
Normally, the NMT enzymes add a fatty acid to the end of certain proteins in a reaction called myristoylation, explained Marc B. Hershenson, MD, Huetwell Professor of Pediatrics and Communicable Diseases and professor of molecular and integrative physiology at the University of Michigan Medical School, Ann Arbor. "Myristoylation is a common modification that allows proteins to interact with other proteins or lipids, which is needed for membrane targeting and various signal transduction pathways."
Drugs targeting myristoylation have been investigated since 1989, Hershenson added.
Taking advantage of those past efforts, Mousnier and colleagues used a high-throughput screen to test small-molecule inhibitors developed against NMT enzymes from fungi and parasites. They reasoning that if they could find an existing molecule with low affinity for the human NMT enzymes, they could then optimize it.
As predicted, they identified two small-molecule inhibitors of NMT from Plasmodium falciparum, which causes malaria. They combined those into a single compound and further tweaked its conformation, following the changes via x-ray crystallography, until it fit snugly into the human enzyme's active site. The resulting IMP-1088 is more than 100 times as potent as the starting molecules from which it is built.
The new drug, IMP-1088, intervenes at the final step of viral replication, when new viral RNA genomes are packaged into the capsid and, thus, halts infection.
To model respiratory infections, the investigators tested IMP-1088 in primary cultures of human bronchial epithelium. The drug worked and was effective even if introduced 3 hours after infection begins or in the presence of corticosteroids typically inhaled to treat asthma and chronic obstructive pulmonary disease, which would be important in patient care.
The investigators also found that IMP-1088 inhibited a range of rhinovirus serotypes as well as poliovirus and foot-and-mouth disease virus. And the fact that the inhibitor targets a human protein and not the virus itself minimizes the likelihood of the emergence of resistant viral strains.
"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," said team leader Edward Tate, PhD, from the Department of Chemistry at Imperial College London in a news release.
But the researchers caution that toxicity testing is necessary and they are still a ways off from human trials.
To that point, Hershenson noted that many human proteins, involved in diverse, essential cellular processes, are myristoylated. "It is therefore likely that NMT inhibitors will have off-target effects on different organ systems, and therefore perhaps side effects. So I'm afraid we are a long way off from a cure for the common cold."
Several coauthors are inventors on a patent application that describes NMT inhibitors, including IMP-1088. The other authors and Hershenson have disclosed no relevant financial relationships.
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SOURCE: May 18, 2018. Nat Chem. Published online May 14, 2018.