Browsing by Author "Salminen, Petja"

Coronavirus disease 2019 (COVID-19) is still considered a global pandemic with novel immunoevasive variants constituting a potential threat to life for many susceptible individuals. Despite successful vaccination programmes, which ensued in early 2020, spread of the virus is still an unresolved issue. To address this, innovative prophylactic approaches are being continuously investigated to target the causative agent of COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Prevention of infection primarily focuses on the targeting of the receptor-binding domain (RBD) on the spike protein of SARS-CoV-2, which is used to infect host cells presenting angiotensin-converting enzyme 2 (ACE2) on their surface. In 2023, a novel antibody mimetic targeting scaffold, namely the sherpabody platform (SH3; src-homology 3; Recombinant Protein Affinity), was introduced. Accordingly, an intranasally administered, RBD targeting trimeric sherpabody, TriSb92, was demonstrated to prevent infection by SARS-CoV-2 and its recent variants of concern by targeting a conserved region within the spike RBD in vitro and in vivo. This study was performed to further investigate and develop the use of sherpabodies in SARS-CoV-2 prophylaxis. Various homo- and heteromultimeric constructs were assembled and the efficiency of their bacterial production was assessed. Additionally, their functionality, specificity and avidity was analysed. Specifically, the combination of different functionalities within a single molecule – receptor blocking and fusion prevention – was studied. Newly discovered RBD-targeting sherpabodies assembled into multimers were able to neutralize SARS-CoV-2 variants, including the latest Omicron subvariants BA.2.75.2 and XBB.1.5. These multimeric sherpabodies were shown to be easily manufacturable, highly target-specific and multifunctional when desired, making them excellent candidates for intranasally administered SARS-CoV-2 prophylaxis.