RESUMO
Containment of the COVID-19 pandemic requires reducing viral transmission. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is initiated by membrane fusion between the viral and host cell membranes, which is mediated by the viral spike protein. We have designed lipopeptide fusion inhibitors that block this critical first step of infection and, on the basis of in vitro efficacy and in vivo biodistribution, selected a dimeric form for evaluation in an animal model. Daily intranasal administration to ferrets completely prevented SARS-CoV-2 direct-contact transmission during 24-hour cohousing with infected animals, under stringent conditions that resulted in infection of 100% of untreated animals. These lipopeptides are highly stable and thus may readily translate into safe and effective intranasal prophylaxis to reduce transmission of SARS-CoV-2.
Assuntos
COVID-19/transmissão , Lipopeptídeos/administração & dosagem , Fusão de Membrana/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , Inibidores de Proteínas Virais de Fusão/administração & dosagem , Internalização do Vírus/efeitos dos fármacos , Administração Intranasal , Animais , COVID-19/prevenção & controle , COVID-19/virologia , Chlorocebus aethiops , Modelos Animais de Doenças , Desenho de Fármacos , Furões , Lipopeptídeos/química , Lipopeptídeos/farmacocinética , Lipopeptídeos/farmacologia , Camundongos , Profilaxia Pré-Exposição , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Distribuição Tecidual , Células Vero , Inibidores de Proteínas Virais de Fusão/química , Inibidores de Proteínas Virais de Fusão/farmacocinética , Inibidores de Proteínas Virais de Fusão/farmacologiaRESUMO
Recent characterization of broadly neutralizing antibodies (bnAbs) against influenza virus identified the conserved hemagglutinin (HA) stem as a target for development of universal vaccines and therapeutics. Although several stem bnAbs are being evaluated in clinical trials, antibodies are generally unsuited for oral delivery. Guided by structural knowledge of the interactions and mechanism of anti-stem bnAb CR6261, we selected and optimized small molecules that mimic the bnAb functionality. Our lead compound neutralizes influenza A group 1 viruses by inhibiting HA-mediated fusion in vitro, protects mice against lethal and sublethal influenza challenge after oral administration, and effectively neutralizes virus infection in reconstituted three-dimensional cell culture of fully differentiated human bronchial epithelial cells. Cocrystal structures with H1 and H5 HAs reveal that the lead compound recapitulates the bnAb hotspot interactions.
Assuntos
Anticorpos Neutralizantes/química , Materiais Biomiméticos/farmacologia , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Influenza Humana/prevenção & controle , Piperazinas/farmacologia , Piridinas/farmacologia , Tetrazóis/farmacologia , Inibidores de Proteínas Virais de Fusão/farmacologia , Internalização do Vírus/efeitos dos fármacos , Administração Oral , Animais , Materiais Biomiméticos/administração & dosagem , Materiais Biomiméticos/farmacocinética , Brônquios/virologia , Células Cultivadas , Cães , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Humanos , Células Madin Darby de Rim Canino , Camundongos , Piperazinas/administração & dosagem , Piperazinas/farmacocinética , Piridinas/administração & dosagem , Piridinas/farmacocinética , Mucosa Respiratória/virologia , Tetrazóis/administração & dosagem , Tetrazóis/farmacocinética , Inibidores de Proteínas Virais de Fusão/administração & dosagem , Inibidores de Proteínas Virais de Fusão/farmacocinéticaRESUMO
New therapeutic alternatives to fight against the spread of HIV-1 are based on peptides designed to inhibit the early steps of HIV-1 fusion in target cells. However, drawbacks, such as bioavailability, short half-life, rapid clearance, and poor ability to cross the physiological barriers, make such peptides unattractive for the pharmaceutical industry. Here we developed, optimized, and characterized polymeric nanoparticles (NPs) coated with glycol chitosan to incorporate and release an HIV-1 fusion inhibitor peptide (E1) inside the vaginal mucosa. The NPs were prepared by a modified double emulsion method, and optimization was carried out by a factorial design. In vitro, ex vivo, and in vivo studies were carried out to evaluate the optimized formulation. The results indicate that the physicochemical features of these NPs enable them to incorporate and release HIV fusion inhibitor peptides to the vaginal mucosa before the fusion step takes place.