We are in the midst of a golden age of uncovering defense systems against bacteriophages. Apart from the fundamental interest in these defense systems, and revolutionary applications that have been derived from them (e.g. CRISPR-Cas9 and restriction endonucleases), it is unknown how defense systems contribute to resistance formation against bacteriophages in clinical settings. Bacteriophages are now being reconsidered as therapeutic agents against bacterial infections due the emergence of multidrug resistance. However, bacteriophage resistance through defense systems and other means could hinder the development of successful phage-based therapies. Here we review the current state of the field of bacteriophage defense, highlight the relevance of bacteriophage defense for potential clinical use of bacteriophages as therapeutic agents, and suggest new directions of research.
Influenza A viruses pose a serious pandemic risk, while generation of efficient vaccines against seasonal variants remains challenging. There is thus a pressing need for new treatment options. We report here a set of macrocyclic peptides that inhibit influenza A virus infection at low nanomolar concentrations by binding to hemagglutinin, selected using ultrahigh-throughput screening of a diverse peptide library. The peptides are active against both H1 and H5 variants, with no detectable cytotoxicity. Despite the high sequence diversity across hits, all tested peptides were found to bind to the same region in the hemagglutinin stem by HDX-MS epitope mapping. A mutation in this region identified in an escape variant confirmed the binding site. This stands in contrast to the immunodominance of the head region for antibody binding and suggests that macrocyclic peptides from in vitro display may be well suited for finding new druggable sites not revealed by antibodies. Functional analysis indicates that these peptides stabilize the prefusion conformation of the protein and thereby prevent virus–cell fusion. High-throughput screening of macrocyclic peptides is thus shown here to be a powerful method for the discovery of novel broadly acting viral fusion inhibitors with therapeutic potential.
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