SARS-CoV-2 Fusion Peptide Conjugated to a Tetravalent Dendrimer Selectively Inhibits Viral Infection

- Fusion is a key event for enveloped viruses, through which viral and cell membranes come into close contact. This event is mediated by viral fusion proteins, which are divided into three structural and functional classes. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein belongs to class I fusion proteins, characterized by a trimer of helical hairpins and an internal fusion peptide (FP), which is exposed once fusion occurs. Many efforts have been directed at finding antivirals capable of interfering with the fusion mechanism, mainly by designing peptides on the two heptad-repeat regions present in class I viral fusion proteins. Here, we aimed to evaluate the anti-SARS-CoV-2 activity of the FP sequence conjugated to a tetravalent dendrimer through a classical organic nucleophilic substitution reaction (SN2) using a synthetic bromoacetylated peptide mimicking the FP and a branched scaffold of poly-L-Lysine functionalized with cysteine residues. We found that the FP peptide conjugated to the dendrimer, unlike the monomeric FP sequence, has virucidal activity by impairing the attachment of SARS-CoV-2 to cells. Furthermore, we found that the peptide dendrimer does not have the same effects on other coronaviruses, demonstrating that it is selective against SARS-CoV-2. AD - Univ Campania Luigi Vanvitelli, Dept Expt Med, Div Pharmacol, I-80138 Naples, Italy AD - Natl Res Council CNR, Inst Biostruct & Bioimaging IBB, I-80134 Naples, Italy AD - Univ Cagliari, Dept Chem & Geol Sci, Univ Campus, I-09042 Cagliari, Italy AD - Univ Cagliari, Dept Biomed Sci, I-09042 Cagliari, Italy AD - Univ Hosp Campania Luigi Vanvitelli, UOC Virol & Microbiol, I-80138 Naples, Italy C3 - Universita della Campania Vanvitelli C3 - Consiglio Nazionale delle Ricerche (CNR) C3 - Istituto di Biostrutture e Bioimmagini (IBB-CNR) C3 - University of Cagliari C3 - University of Cagliari