Potent peptidic fusion inhibitors of influenza virus

Kadam, Rameshwar U.; Juraszek, Jarek; Brandenburg, Boerries; Buyck, Christophe; Schepens, Wim; Kesteleyn, Bart; Stoops, Bart; Vreeken, Rob J.; Vermond, Jan; Goutier, Wouter; Tang, Chan; Vogels, Ronald; Friesen, Robert H.; Goudsmit, Jaap; Dongen, M.J.P. van; Wilson, Ian A.

doi:10.1126/science.aan0516

Cited by 143 publications

(156 citation statements)

References 40 publications

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“…The structures of HA in complex with broadly neutralizing antibodies targeting the conserved stem region (Ekiert et al, 2009) (Figure 2), which neutralize by blocking the fusogenic conformational change, have shown us how to use the complementarity determining region of the bound antibodies to design small proteins targeting the same site (Fleishman et al, 2011). Further studies identified small peptides targeting this site, with the same potent inhibitory effect (Kadam et al, 2017). These results suggest that it may be possible to identify non-peptidic, orally bioavailable antiviral compounds using the same strategy to treat flu infections.…”

Section: Discussionmentioning

confidence: 99%

Common Features of Enveloped Viruses and Implications for Immunogen Design for Next-Generation Vaccines

Rey

Lok

2018

Cell

204

216

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Enveloped viruses enter cells by inducing fusion of viral and cellular membranes, a process catalyzed by a specialized membrane-fusion protein expressed on their surface. This review focuses on recent structural studies of viral fusion proteins with an emphasis on their metastable prefusion form and on interactions with neutralizing antibodies. The fusion glycoproteins have been difficult to study because they are present in a labile, metastable form at the surface of infectious virions. Such metastability is a functional requirement, allowing these proteins to refold into a lower energy conformation while transferring the difference in energy to catalyze the membrane fusion reaction. Structural studies have shown that stable immunogens presenting the same antigenic sites as the labile wild-type proteins efficiently elicit potently neutralizing antibodies, providing a framework with which to engineer the antigens for stability, as well as identifying key vulnerability sites that can be used in next-generation subunit vaccine design.

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Section: Discussionmentioning

confidence: 99%

Common Features of Enveloped Viruses and Implications for Immunogen Design for Next-Generation Vaccines

Rey

Lok

2018

Cell

204

216

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“…Two other stem-binding bnAbs, FI6v3 44 and 39.29 58 of the V H 3–30 germline family, which bind the HA at a very different angle and use both light and heavy chains for interaction, compared to V H 1–69, where the heavy chain makes the majority, if not all, of the stem interactions. Nonetheless, V H 1–69 and V H 3–30 antibodies have very similar binding footprints and fill the same set of hydrophobic pockets in the HA stem 59 . However, the V H 3–30 family uses an extended CDR H3 to occupy the same pockets as the IFY motif of the V H 1–69 antibodies.…”

Section: Design Of a More Universal Vaccinementioning

confidence: 97%

“…In another recent breakthrough, small peptides were designed and characterized against this same site in the HA stem, also based on how bnAbs target the stem, in a collaboration between Janssen and our laboratory 59 . Using the CDR interacting loops of two bnAbs FI6v3 and CR9114 as templates, cyclic peptides that also incorporated non-proteinogenic amino acids were designed to fill the same hydrophobic pockets in the HA stem as the stem-binding bnAbs 59 .…”

Section: Design Of Small Proteins and Peptides Against The Ha Stem Domentioning

confidence: 99%

“…Using the CDR interacting loops of two bnAbs FI6v3 and CR9114 as templates, cyclic peptides that also incorporated non-proteinogenic amino acids were designed to fill the same hydrophobic pockets in the HA stem as the stem-binding bnAbs 59 . The crystal structure of one of these peptides, P7, confirmed that it indeed targets exactly the same highly conserved region in the stem as the bnAbs.…”

Section: Design Of Small Proteins and Peptides Against The Ha Stem Domentioning

confidence: 99%

“…Four different designs that target the HA stem region, namely HB36.3 (PDB 3R2X) 72 , HB80.4 (PDB 4EEF) 73 , HB1.6928.2.3 (PDB 5VLI) 74 , and P7 (PDB 5W6T) 59 , along with CR9114 Fab (PDB 3GBM) 40 are shown in burgundy. HA is colored white.…”

Section: Figurementioning

confidence: 99%

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Structural insights into the design of novel anti-influenza therapies

Wilson

2018

Nat Struct Mol Biol

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A limited arsenal of therapies is available to tackle the emergence of a future influenza pandemic or even to effectively deal with the continual outbreaks of seasonal influenza. However, recent findings hold great promise for design of novel vaccines and therapeutics, including the possibility of more universal treatments. A major contribution to those advances comes from structural biology, in particular from the many studies on influenza hemagglutinin (HA), the major surface antigen. The HA primary function is to enable the virus to enter host cells, and structural work has revealed the various HA conformational forms generated during the entry process. Other studies have explored how human broadly neutralizing antibodies (bnAbs), designed proteins, peptides and small molecules, can inhibit and neutralize the virus. Here we review milestones in HA structural biology and how the recent insights from broadly neutralizing antibodies are leading to design of novel vaccines and therapeutics.

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Molecular Complementarity of Proteomimetic Materials for Target‐Specific Recognition and Recognition‐Mediated Complex Functions

Kim

Jung

et al. 2023

Advanced Materials

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transduction to enable survival and adaption. They are composed of long folded chains made up of a variety of 20 different α-amino acids, which form elaborate molecular structures. These structures can then fit counterpart molecules via molecular complementarity, thus enabling them to perform their specific cellular functions (Figure 1). For instance, membrane receptors specifically recognize extracellular ligand molecules and transfer desired molecular signals into the cell across the ligand-impermeable membrane. [1][2][3] Moreover, different membrane channels exist at the cell surface; in response to external stimuli such as pH, temperature, and action potentials, they undergo conformational changes to modulate the permeability of specific ions and metabolites. [4][5][6] The received extracellular signals are then converted into appropriate cellular responses; this process involves the intracellular increase of certain molecules to control transcription factors and regulate gene expression. [7,8] Even within the cell, there are various proteinligand interactions; for example, some metabolites can bind transcription factors, allosterically regulating subsequent transcription by RNA polymerases. [9,10] To manage cellular metabolism, enzymes catalyze more than 5000 biochemical reactions under highly limited physiological conditions (e.g., mild temperature, neutral pH, and low salt concentrations), attributed to their specific substrate binding abilities and effective collaboration with cofactors or coenzymes. [11] The availability of proteins that interact with many different targets benefits a broad range of biological and biotechnological research. Due to the functional diversity and specificity of the proteins, synthetic biology has successfully refined and rewired various cellular functions to solve numerous issues in a diverse range of fields such as agriculture, [12] manufacturing, [13] pharmaceutics, [14] and therapeutics. [15,16] For example, the use of proteins that enable gene recognition and editing has contributed to the emergence of important metabolic and genetic engineering techniques, allowing for the modulation of microbial cell factories that can efficiently produce high-value products, including biofuels, [17] medicines, [14] and biomolecules for industrial use. [18] Moreover, genetically encoded signal transducers As biomolecules essential for sustaining life, proteins are generated from long chains of 20 different α-amino acids that are folded into unique 3D structures. In particular, many proteins have molecular recognition functions owing to their binding pockets, which have complementary shapes, charges, and polarities for specific targets, making these biopolymers unique and highly valuable for biomedical and biocatalytic applications. Based on the understanding of protein structures and microenvironments, molecular complementarity can be exhibited by synthesizable and modifiable materials. This has prompted researchers to explore the proteomimetic potentials of a diverse range of material...

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Potent peptidic fusion inhibitors of influenza virus

Cited by 143 publications

References 40 publications

Common Features of Enveloped Viruses and Implications for Immunogen Design for Next-Generation Vaccines

Common Features of Enveloped Viruses and Implications for Immunogen Design for Next-Generation Vaccines

Structural insights into the design of novel anti-influenza therapies

Molecular Complementarity of Proteomimetic Materials for Target‐Specific Recognition and Recognition‐Mediated Complex Functions

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