Research Article

Potent peptidic fusion inhibitors of influenza virus

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Science  27 Oct 2017:
Vol. 358, Issue 6362, pp. 496-502
DOI: 10.1126/science.aan0516

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Broadly reactive drugs for flu

Drugs for influenza are limited. For those available, viral resistance is rife. Part of the problem is that the virus is constantly mutating. Kadam et al. tested the cell entry stage of the virus life cycle as a drug target (see the Perspective by Whitehead). Cell entry is mediated by the major surface glycoprotein hemagglutinin (HA). This stage can be blocked by broadly neutralizing antibodies binding to HA. The authors generated small cyclic peptides that bind to the same sites on HA as the antibodies and mimic their activity. The peptides are cheap and easy to synthesize, are nontoxic to mice, and prevented infection of cells by many types of influenza virus.

Science, this issue p. 496; see also p. 450

Abstract

Influenza therapeutics with new targets and mechanisms of action are urgently needed to combat potential pandemics, emerging viruses, and constantly mutating strains in circulation. We report here on the design and structural characterization of potent peptidic inhibitors of influenza hemagglutinin. The peptide design was based on complementarity-determining region loops of human broadly neutralizing antibodies against the hemagglutinin (FI6v3 and CR9114). The optimized peptides exhibit nanomolar affinity and neutralization against influenza A group 1 viruses, including the 2009 H1N1 pandemic and avian H5N1 strains. The peptide inhibitors bind to the highly conserved stem epitope and block the low pH–induced conformational rearrangements associated with membrane fusion. These peptidic compounds and their advantageous biological properties should accelerate the development of new small molecule– and peptide-based therapeutics against influenza virus.

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