Biology subjects

Diaz Avalos, R.

Publications and source records attributed to Diaz Avalos, R..

3 recordsLinked to original sources

bioRxiv2024

A broadly-neutralizing antibody against Ebolavirus glycoprotein that potentiates the breadth and neutralization potency of other antibodies

Ebolavirus disease (EVD) is caused by multiple species of Ebolavirus. Monoclonal antibodies (mAbs) against the virus glycoprotein (GP) are the only class of therapeutic approved for treatment of EVD caused by Zaire ebolavirus (EBOV). Therefore, mAbs targeting multiple Ebolavirus species may represent the next generation of EVD therapeutics. Broadly reactive anti-GP mAbs were produced; among these, mAbs 11886 and 11883 were broadly neutralizing in vitro. A 3.0 [A] cryo-electron microscopy structure of EBOV GP bound to both mAbs shows that 11886 binds a novel epitope bridging the glycan cap (GC), 310 pocket and GP2 N-terminus, whereas 11883 binds the receptor binding region (RBR) and GC. In vitro, 11886 synergized with a range of mAbs with epitope specificities spanning the RBR/GC, including 11883. Notably, 11886 increased the breadth of neutralization by partner mAbs against different Ebolavirus species. These data provide a strategic route to design improved mAb-based next-generation EVD therapeutics.

immunology↗

bioRxiv2022

Structural basis for antibody-mediated neutralization of Lymphocytic choriomeningitis virus

The mammarenavirus Lymphocytic choriomeningitis virus (LCMV) is a globally distributed zoonotic pathogen that can be lethal in immunocompromised patients and cause severe birth defects if acquired during pregnancy. Despite the fundamental importance of LCMV for studying immunobiology, the structure of the trimeric surface glycoprotein, essential for entry, vaccine design and antibody neutralization, remains unknown. In this study, we present the cryoEM structure of the LCMV surface glycoprotein (GP) in its trimeric prefusion assembly both alone and in complex with a rationally engineered monoclonal neutralizing antibody termed 18.5C-M28 (M28). Additionally, we show that passive administration of M28 protects mice from LCMV clone 13 (LCMVcl13) challenge when administered as either a prophylactic or therapeutic. Our study illuminates not only the overall structural organization of LCMV GP and the mechanism for its inhibition by M28, but also presents a promising therapeutic candidate to prevent severe or fatal disease in individuals who are at risk of infection by a virus that poses a threat worldwide. HighlightsO_LIRationally-engineered antibody M28 neutralizes lymphocytic choriomeningitis virus in vitro. C_LIO_LIFirst high-resolution cryoEM structure of the pre-fusion trimeric lymphocytic choriomeningitis virus glycoprotein alone and in complex with M28. C_LIO_LIM28 neutralizes by bridging adjacent glycoprotein protomers and locking it in the pre-fusion state. C_LIO_LIProphylactic and therapeutic administration of M28 protects mice from chronic lymphocytic choriomeningitis virus infection. C_LI

microbiology↗

bioRxiv2021

Structure-based design of a highly stable, covalently-linked SARS-CoV-2 spike trimer with improved structural properties and immunogenicity

The continued threat of SARS-CoV-2 to global health necessitates development of improved research tools and vaccines. We present an improved SARS-CoV-2 spike ectodomain, "VFLIP", bearing five proline substitutions, a flexible cleavage site linker, and an inter-protomer disulfide bond. VFLIP displays significantly improved stability, high-yield production and retains its trimeric state without exogenous trimerization motifs. High-resolution cryo-EM and glycan profiling reveal that the VFLIP quaternary structure and glycosylation mimic the native spike on the viral surface. Further, VFLIP has enhanced affinity and binding kinetics relative to other stabilized spike proteins for antibodies in the Coronavirus Immunotherapeutic Consortium (CoVIC), and mice immunized with VFLIP exhibit potent neutralizing antibody responses against wild-type and B.1.351 live SARS-CoV-2. Taken together, VFLIP represents an improved tool for diagnostics, structural biology, antibody discovery, and vaccine design.

microbiology↗