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. 2020 Feb 5;142(5):2140-2144.
doi: 10.1021/jacs.9b11548. Epub 2020 Jan 23.

Structure-Guided Improvement of a Dual HPIV3/RSV Fusion Inhibitor

Victor K Outlaw  1 , Jennifer T Lemke  1 , Yun Zhu  2   3 , Samuel H Gellman  1 , Matteo Porotto  2   4   5 , Anne Moscona  2   4   6   7
Affiliations

Structure-Guided Improvement of a Dual HPIV3/RSV Fusion Inhibitor

Victor K Outlaw et al. J Am Chem Soc. .

Abstract

Human parainfluenza virus 3 (HPIV3) and respiratory syncytial virus (RSV) are leading causes of lower respiratory tract infections. There are currently no vaccines or antiviral therapeutics to treat HPIV3 or RSV infections. We recently reported a peptide (VIQKI), derived from the C-terminal heptad repeat (HRC) domain of the HPIV3 fusion (F) glycoprotein that inhibits infection by both HPIV3 and RSV. The dual inhibitory activity of VIQKI is due to its unique ability to bind to the N-terminal heptad repeat (HRN) domains of both HPIV3 and RSV F, thereby preventing the native HRN-HRC interactions required for viral entry. Here we describe the structure-guided design of dual inhibitors of HPIV3 and RSV fusion with improved efficacy. We show that VIQKI derivatives possessing one (I456F) or two (I454F/I456F) phenylalanine substitutions near the N-terminus exhibit more stable assemblies with the RSV-HRN domain and enhanced antiviral efficacy against both HPIV3 and RSV infection. Cocrystal structures of the new Phe-substituted inhibitors coassembled with HPIV3 or RSV-HRN domains reveal that the I456F substitution makes intimate hydrophobic contact with the core trimers of both HPIV3 and RSV F.

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Figures

Figure 1.
Figure 1.
Domain architecture and structures of HPIV3 and RSV F. (A) Diagram of HPIV3 and RSV F with fusion peptide (FP), N-terminal (HRN) and C-terminal (HRC) heptad repeat, and transmembrane (TM) domains. Structures of pre-fusion (B, PDB:4MMV) and post-fusion (C, PDB:3RRR) conformations of RSV F. (D) Peptide sequences for HPIV3-HRC, RSV-HRC, VIQKI-I456F, and VIQKI-I454F/I456F (Phe-substitutionsv in red).
Figure 2.
Figure 2.
HRC domain N-terminal segments in six-helix bundle assemblies. X-ray structures of (A) the full 6HB HPIV3-HRN+VIQKI (PDB:6NRO) with magnified images of (B) HPIV3-HRN+VIQKI, (C) post-fusion RSV F (PDB:3RRR), and (D) RSV-HRN+VIQKI (PDB:6NTX).
Figure 3.
Figure 3.
Antiviral efficacy of VIQKI-I456F and VIQKI-I454F/I456F against RSV or HPIV3. Peptide activity against (A) RSV or (B) HPIV3 was determined by plaque-reduction assay in infected Hep-2 cell monolayers. Data are expressed as mean ± standard deviation (n=3 separate experiments).
Figure 4.
Figure 4.
X-ray structures of (A) 6HB segment of RSV F in post-fusion conformation (PDB:3RRR) and co-crystal structures of (B) RSV-HRN+VIQKI-I456F (PDB:6OJ7) and (C) HPIV3-HRN+VIQKI-I454F/I456F (PDB:6O40). The phenylalanine-substituted VIQKI analogs adopt a binding mode similar to that of RSV-HRC. Colors correspond to RSV-HRN (salmon), HPIV3-HRN (orange), RSV-HRC (yellow), and VIQKI/VIQKI-I456F/VIQKI-I454F/I456F (green with Phe-substitutions in violet). Electrostatic potential maps at the binding site of (D) Phe488 (RSV F), (E) Phe456 (RSV-HRN+VIQKI-I456F), and (F) Phe456 (HPIV3-HRN+VIQKI-I454F/I456F) with anionic (red), neutral (gray), or positive (blue) charge density.
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