Targeted photodynamic neutralization of SARS-CoV-2 mediated by singlet oxygen

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has been on a rampage for more than two years. Vaccines in combination with neutralizing antibodies (NAbs) against SARS-CoV-2 carry great hope in the treatment and final elimination of coronavirus disease 2019 (COVID-19). However, the relentless emergence of variants of concern (VOC), including the most recent Omicron variants, presses for novel measures to counter these variants that often show immune evasion. Hereby we developed a targeted photodynamic approach to neutralize SARS-CoV-2 by engineering a genetically encoded photosensitizer (SOPP3) to a diverse list of antibodies targeting the wild-type (WT) spike protein, including human antibodies isolated from a 2003 Severe acute respiratory syndrome (SARS) patient, potent monomeric and multimeric nanobodies targeting receptor-binding domain (RBD), and non-neutralizing antibodies (non-NAbs) targeting the more conserved N-terminal domain (NTD). As confirmed by pseudovirus neutralization assay, this targeted photodynamic approach significantly increased the efficacy of these antibodies, especially that of non-NAbs, against not only the WT but also the Delta strain and the heavily immune escape Omicron strain (BA.1). Subsequent measurement of infrared phosphorescence at 1270 nm confirmed the generation of singlet oxygen ( 1 O 2 ) in the photodynamic process. Mass spectroscopy assay uncovered amino acids in the spike protein targeted by 1 O 2 . Impressively, Y145 and H146 form an oxidization “hotspot”, which overlaps with the antigenic “supersite” in NTD. Taken together, our study established a targeted photodynamic approach against the SARS-CoV-2 virus and provided mechanistic insights into the photodynamic modification of protein molecules mediated by 1 O 2 . Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s43630-023-00381-w.

Photodynamic Therapy Applications in Cancer, Infections and Cardiovascular Disease

“…As confirmed by the pseudovirus neutralization assay, this targeted photodynamic approach significantly increased the efficacy of these antibodies, not only against the WT but also the Delta and Omicron strains. Measurement of infrared phosphorescence at 1270 nm confirmed the presence of singlet oxygen ( 1 O 2 ) generated in the photodynamic pro-cess [127].…”

The development and application of pseudoviruses: assessment of SARS-CoV-2 pseudoviruses

“…LS-BB2z, a multivalent nanobody constructed by lumazine protein nanobody binding platform and monovalent nanobody, has enhanced the monovalent nanobody’s ability to neutralize the pseudovirus ( Lu et al, 2023 ). A genetically encoded photosensitizer SOPP3 enhanced the neutralization efficacy of antibodies against S proteins and was effective against WT SARS-CoV-2, Delta, and Omicron variants ( Yao et al, 2023 ). In addition, PBNA has also been used to locate specific mutations of variants that affect the neutralizing effect of antibodies to provide insight into the mechanisms of antibody resistance.…”

Membrane-Targeting Perylenylethynylphenols Inactivate Medically Important Coronaviruses via the Singlet Oxygen Photogeneration Mechanism

“…The 1 O2-induced formation of short polar lipids dramatically changes the membrane rheology, and, in the case of virion envelopes, their ability to fuse with the host cellular membrane [23,24]. Generally, membrane-targeting 1 O2-generating compounds show remarkable antiviral effects in vitro, e.g., arylidene rhodanines (LJ compounds) [25][26][27][28], methylene blue [29][30][31][32], riboflavin derivatives [33], iodinated BODIPY [34], fullerene derivatives [35], phthalocyanines [36][37][38], pheophorbide a [39] and other porphyrins [40][41][42], AIE compounds [43], alkyl Rose Bengal derivatives [44], and a genetically encoded photosensitizer [45].…”