Human parainfluenza virus 3 (HPIV3) and respiratory syncytial virus (RSV) cause lower respiratory infection in infants and young children. There are no vaccines for these pathogens, and existing treatments have limited or questionable efficacy. Infection by HPIV3 or RSV requires fusion of the viral and cell membranes, a process mediated by a trimeric fusion glycoprotein (F) displayed on the viral envelope. Once triggered, the pre-fusion form of F undergoes a series of conformational changes that first extend the molecule to allow for insertion of the hydrophobic fusion peptide into the target cell membrane and then refold the trimeric assembly into an energetically stable post-fusion state, a process that drives the merger of the viral and host cell membranes. Peptides derived from defined regions of HPIV3 F inhibit infection by HPIV3 by interfering with the structural transitions of the trimeric F assembly. Here we describe lipopeptides derived from the C-terminal heptad repeat (HRC) domain of HPIV3 F that potently inhibit infection by both HPIV3 and RSV. The lead peptide inhibits RSV infection as effectively as does a peptide corresponding to the RSV HRC domain itself. We show that the inhibitors bind to the N-terminal heptad repeat (HRN) domains of both HPIV3 and RSV F with high affinity. Co-crystal structures of inhibitors bound to the HRN domains of HPIV3 or RSV F reveal remarkably different modes of binding in the N-terminal segment of the inhibitor.

BACKGROUND:Postintensive care syndrome (PICS) has been identified in a large proportion of medical intensive care unit survivors; however, the occurrence surgical intensive care unit (SICU) survivors is unknown. We implemented a multidisciplinary critical care outpatient clinic (CCOC) to identify the occurrence of PICS in SICU survivors. METHODS:Seventy acute care surgery and trauma patients, 18 years or older, who remained in the SICU for 72 hours or longer at a Level I trauma center were seen in CCOC at 2 weeks, 12 weeks, and 24 weeks after hospital discharge. The CCOC staffing included a nurse coordinator, social worker, critical care pharmacist, physical therapist, and acute care surgeon who identified PICS sequelae in their respective specialties by clinical criteria and screening questionnaires. RESULTS:Of 82 eligible patients, 70 (85.4%) were seen at least once for 116 total visits. Forty-three (61.4%) patients suffered traumatic injuries and 27 (38.6%) underwent emergent general surgery. Sixty-seven (95.7%) demonstrated at least one PICS criterion. Over all visits, 26 (37.1%) patients presented with one PICS criterion, 24 (34.3%) patients with two, and 17 (24.3%) with three. Cognitive impairment was observed in 29 (41.4%) patients, psychiatric in 30 (42.9%), and physical symptoms in 65 (92.9%). Activity Measure for Post-Acute Care scores improved from severe impairment at admission to full function by 12 weeks postdischarge, yet 6 Minute Walk Test scores remained below age-matched references through all visits. Patients expressed mild to moderate depression based on Patient Health Questionnaire-9 scores. A medication reconciliation was completed at 96.5% (112/116) of the visits with 116 total medication recommendations. By 24 weeks following discharge, only 26.4% (14/53) of previously employed patients had resumed work. CONCLUSION:Through the successful implementation of a multidisciplinary CCOC, this study identifies an exorbitant rate of PICS among SICU survivors.

Paramyxoviruses, including human parainfluenza virus type 3, are internalized into host cells by fusion between viral and target cell membranes. The receptor binding protein, hemagglutinin-neuraminidase (HN), and the fusion protein (F) facilitate viral fusion and entry into cells through a process involving HN activation by receptor binding, which triggers conformational changes in F to activate it to reach its fusion-competent state. Interfering with this process through premature activation of the F protein may be an effective antiviral strategy in vitro. We identified and optimized small compounds that implement this antiviral strategy through an interaction with HN, causing HN to activate F in an untimely fashion. To address that mechanism, we produced novel anti-HPIV3 F conformation-specific antibodies that can be used to assess the functionality of compounds designed to induce F activation. Both the novel antiviral compounds that we present and these newly characterized postfusion antibodies are novel tools for the exploration and development of antiviral approaches.