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Drug Discovery

Agent stops common cold virus replication

In cells, inhibitor created by fragment-based drug design prevents rhinovirus from reproducing

by Stu Borman
May 17, 2018 | A version of this story appeared in Volume 96, Issue 21

Rhinoviruses cause common colds and worsen symptoms of asthma, chronic obstructive pulmonary disease, and cystic fibrosis. No specific approved treatments for the viruses are currently available, but a new study may offer hope.

Edward W. Tate and Roberto Solari of Imperial College London and coworkers have now identified a small molecule, IMP-1088, that prevents rhinovirus reproduction by inhibiting a human enzyme called N-myristoyltransferase (Nat. Chem. 2018, DOI: 10.1038/s41557-018-0039-2).

When rhinovirus infects the body, it hijacks the host genome to produce proteins it needs. For instance, to construct the shell, or capsid, it needs to reproduce, it relies on the human enzyme to add a lipid to a viral capsid protein. Inhibiting the human enzyme thus prevents viral replication.

Crystal structures and other evidence showed that two inhibitors the researchers identified early in their study hit two different sites in the human enzyme. They used fragment-based drug design to join the two inhibitors and structure-guided design to tweak the combination agent’s drug properties, yielding IMP-1088.

In infected human cells, IMP-1088 blocked myristoylation, viral replication, and infectivity without being toxic to the cells. The compound has nanomolar antiviral activity against multiple rhinovirus strains.

To be effective, IMP-1088 must be administered to cells within hours of infection. In vivo studies have not been done yet so the researchers don’t know whether this time window will also apply in animals or people. A potential advantage of the approach is that viruses might have difficulty developing resistance to a drug that targets a human enzyme, the researchers say.

Hong Wei Chu, an expert in airway cell biology and viral infections at leading respiratory hospital National Jewish Health comments that animal and clinical trials are needed because “multiple immune cells and factors will affect the ultimate therapeutic efficacy of IMP-1088.” However, “overall, the data are novel to the field and likely provide a new approach to prevent or treat rhinovirus infection.”


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