De novo protein design enables the precise induction of RSV-neutralizing antibodies

Abstract

De novo protein design has been successful in expanding the natural protein repertoire. However, most de novo proteins lack biological function, presenting a major methodological challenge. In vaccinology, the induction of precise antibody responses remains a cornerstone for next-generation vaccines. Here, we present a protein design algorithm called TopoBuilder, with which we engineered epitope-focused immunogens displaying complex structural motifs. In both mice and nonhuman primates, cocktails of three de novo–designed immunogens induced robust neutralizing responses against the respiratory syncytial virus. Furthermore, the immunogens refocused preexisting antibody responses toward defined neutralization epitopes. Overall, our design approach opens the possibility of targeting specific epitopes for the development of vaccines and therapeutic antibodies and, more generally, will be applicable to the design of de novo proteins displaying complex functional motifs.

Amino acid interacting network in the receptor-binding domain of SARS-CoV-2 spike protein

“…This new concept and method of AABP for interaction between amino acids is clearly one step beyond the simpler interatomic interactions in proteins. 12 More importantly, the method can be readily applied to and play a crucial role in large-scale computation for protein design [34][35][36][37] and understanding the mutation process [38][39][40] leading to effective vaccine and therapeutic drug design [41][42][43] in combating COVID-19 pandemics. This is because such urgent research topics require the information on the details of the interaction under different environments, involving a single amino acid or clusters of multiple amino acids.…”

Point-of-Care Diagnostics of COVID-19: From Current Work to Future Perspectives

“…Such proteins generally show reduced size, high levels of expression, and high stability. In a recent publication, Sesterhenn et al [125] designed de novo proteins around well-known antigen peptides with the aim to stabilize their structure. It has been shown that such small de novo proteins are able to elicit an immune response, inducing physiologically relevant neutralizing serum levels [125].…”

Flu Universal Vaccines: New Tricks on an Old Virus

“…While most de novo proteins designed so far are either functionless or present functions that are encoded by regular, continuous secondary structures. Interestingly, a great progress has been made recently by Sesterhenn et al, who developed a novel computational design strategy to build de novo proteins presenting complex structural motifs (Sesterhenn et al 2020). By using this strategy, the authors further engineered epitope-focused immunogens mimicking irregular and discontinuous RSV neutralization epitopes.…”

“…By using this strategy, the authors further engineered epitope-focused immunogens mimicking irregular and discontinuous RSV neutralization epitopes. And excitingly, the de novo-designed immunogens can induce robust neutralizing responses against the respiratory syncytial virus in both mice and nonhuman primates (Sesterhenn et al 2020).…”