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 existing 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 RSV HRN domain and enhanced antiviral efficacy against both HPIV3 and RSV infection. Co-crystal structures of the new Phe-substituted inhibitors co-assembled 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.

OBJECTIVES: The purpose of this study was to minimize unnecessary laboratory services for hospitalized neonates with hyperbilirubinemia by revising a local clinical practice pathway (CPP). METHODS: A retrospective cohort study was performed to compare the number of laboratory tests and blood draws in patients hospitalized with neonatal hyperbilirubinemia before and after implementation of a revised CPP. The study included infants with neonatal hyperbilirubinemia <14 days old admitted after their birth hospitalization between April 2017 and October 2019. Primary outcome measures included the total number of blood draws and the number of laboratory tests obtained per patient and length of stay. Secondary outcome measures included 7-day readmission rate, charges, and discharge bilirubin level. RESULTS: The median number of blood draws per patient after implementation of the CPP decreased to 2 (interquartile range [IQR], 2–3) compared with 3 (IQR, 2–3) before implementation (Poisson model–based estimated mean difference, 1.1; 95% confidence interval, 1.0–1.3; P = .018). The median number of laboratory tests per patient after implementation decreased from 4 (IQR, 3–6) to 3 (IQR, 2–4; Poisson model–based estimated mean difference, 1.3; 95% confidence interval, 1.2–1.5; P < .0001). There was no significant change in length of stay, readmission rate, charges, or discharge bilirubin level. CONCLUSIONS: Implementation of a revised CPP was associated with a significant decrease in the number of blood draws and laboratory tests per patient for infants admitted to the hospital for neonatal hyperbilirubinemia.

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 existing 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 RSV HRN domain and enhanced antiviral efficacy against both HPIV3 and RSV infection. Co-crystal structures of the new Phe-substituted inhibitors co-assembled 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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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 existing 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 RSV HRN domain and enhanced antiviral efficacy against both HPIV3 and RSV infection. Co-crystal structures of the new Phe-substituted inhibitors co-assembled 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.