Farnesyltransferase inhibitor lonafarnib suppresses respiratory syncytial virus infection by blocking conformational change of fusion glycoprotein

Respiratory syncytial virus(RSV)is the major cause of bronchiolitis and pneumonia in young children and the elderly.There are currently no approved RSV-specific therapeutic small molecules available.Using high-throughput antiviral screening,we identified an oral drug,the prenylation inhibitor lonafarnib,which showed potent inhibition of the RSV fusion process.Lonafarnib exhibited antiviral activity against both the RSV A and B genotypes and showed low cytotoxicity in HEp-2 and human primary bronchial epithelial cells(HBEC).Time-of-addition and pseudovirus assays demonstrated that lonafarnib inhibits RSV entry,but has farnesyltransferase-independent antiviral efficacy.Cryo-electron microscopy revealed that lonafarnib binds to a triple-symmetric pocket within the central cavity of the RSV F metastable pre-fusion conformation.Mutants at the RSV F sites interacting with lonafarnib showed resistance to lonafarnib but remained fully sensitive to the neutralizing monoclonal antibody palivizumab.Furthermore,lonafarnib dose-dependently reduced the replication of RSV in BALB/c mice.Collectively,lonafarnib could be a potential fusion inhibitor for RSV infection.

A combined virtual impactor and field-effect transistor microsystem for particulate matter separation and detection

Ambient suspended particulate matter(PM)(primarily with particle diameter 2.5m or less,i.e.,PM2.5)can adversely affect ecosystems and human health.Currently,optical particle sensors based on light scattering dominate the portable PM sensing market.However,the light scattering method has poor adaptability to different-sized PM and adverse environmental conditions.Here,we design and develop a portable PM sensing microsystem that consists of a micromachined virtual impactor(VI)for particle separation,a thermophoretic deposition chip for particle collection,and an extended-gate field-effect transistor(FET)for particle analysis.This system can realize on-site separation,collection,and analysis of aerosol particles without being influenced by environmental factors.In this study,the design of the VI is thoroughly analyzed by numerical simulation,and mixtures of different-sized silicon dioxide(SiO2)particles are used in an experimental verification of the performance of the VI and FET.Considering the low cost and compact design of the whole system,the proposed PM analysis microsystem has potential for PM detection under a wide range of conditions,such as heavily polluted industrial environments and for point-of-need outdoor and indoor air quality monitoring.

Development of a novel virus-like particle-based vaccine for preventing tick-borne encephalitis virus infection

Tick-borne encephalitis virus(TBEV)is an important tick-borne pathogen that poses as a serious public health concern.The coverage and immunogenicity of the currently available vaccines against TBEV are relatively low;therefore,it is crucial to develop novel and effective vaccines against TBEV.The present study describes a novel strategy for the assembly of virus-like particles(VLPs)by co-expressing the structural(core/prM/E)and non-structural(NS2B/NS3Pro)proteins of TBEV.The efficacy of the VLPs was subsequently evaluated in C57BL/6 mice,and the resultant IgG serum could neutralize both Far-Eastern and European subtypes of TBEV.These findings indicated that the VLP-based vaccine elicited the production of cross-subtype reactive antibodies.The VLPs provided protection to mice lacking the type I interferon receptor(IFNAR^(-/-))against lethal TBEV challenge,with undetectable viral load in brain and intestinal tissues.Furthermore,the group that received the VLP vaccine did not exhibit significant pathological changes and the inflammatory factors were significantly suppressed compared to the control group.Immunization with the VLP vaccine induced the production of multiple-cytokine-producing antiviral CD4+T cells in vivo,including TNF-α^(+),IL-2^(+),and IFN-γ^(+)T cells.Altogether,the findings suggest that noninfectious VLPs can serve as a potentially safe and effective vaccine candidate against diverse subtypes of TBEV.