RP5: Nanobody therapeutics against henipaviruses, arenaviruses, and structural characterization

Abstract The COVID-19 pandemic has emphasized the pressing need for rapid drug development and novel antiviral therapies. Nanobodies, derived from camelid animals, show promise as small antigen-binding entities capable of recognizing inaccessible epitopes. Their ability to penetrate tissues and cross the blood-brain barrier makes them well-suited for treating viral infections that affect the Central Nervous System (CNS). This project focuses on addressing Henipaviruses (HNV) and arenaviruses (ARV), which pose significant global health risks but lack specific treatments. HNVs can cause severe respiratory and Central Nervous System (CNS) illnesses with high mortality rates. On the other hand, ARV infections are responsible for fatal hemorrhagic fever. Specifically, the study targets Nipah virus (NiV) and Hendra virus (HeV) as prototypes for HNV, as well as Lassa virus (LASV) and Machupo virus (MACV) for ARV. The research aims to develop nanobody-based therapeutic approaches by targeting the viral entry machinery, such as the glycoproteins G and F for HNV and the glycoprotein complex (GPC) for ARV. The project utilizes three nanobody development platforms, including camelid animals, nanomice and human nanobody libraries, to efficiently identify potential nanobody leads. By employing a structure-based approach, the project aims to understand viral neutralization mechanisms, improve nanobody engineering techniques, and design nanobodies capable of effectively penetrating the blood-brain barrier. The specific objectives involve identifying cross-reactive nanobodies for HNVs, developing nanobodies to overcome the glycan shield of ARVs, conducting structural characterization, enhancing nanobody efficacy and CNS bioavailability, and expanding the research to include other viral targets within the HNV and ARV groups in the second phase. Ultimately, the project aims to contribute to the development of effective nanobody-based therapies for HNV and ARV infections, while establishing a generalizable strategy for future emerging viruses with similar characteristics, thereby mitigating the global public health risks associated with these pathogens.