Antiviral fibrils of self-assembled peptides with tunable compositions

Abstract

The lasting threat of viral pandemics necessitates the development of tailorable first-response antivirals with specific but adaptive architectures for treatment of novel viral infections. Here, such an antiviral platform has been developed based on a mixture of hetero-peptides self-assembled into functionalized β-sheets capable of specific multivalent binding to viral protein complexes. One domain of each hetero-peptide is designed to specifically bind to certain viral proteins, while another domain self-assembles into fibrils with epitope binding characteristics determined by the types of peptides and their molar fractions. The self-assembled fibrils maintain enhanced binding to viral protein complexes and retain high resilience to viral mutations. This method is experimentally and computationally tested using short peptides that specifically bind to Spike proteins of SARS-CoV-2. This platform is efficacious, inexpensive, and stable with excellent tolerability.

Structural Consequences of Introducing Bioactive Domains to Designer β-Sheet Peptide Self-Assemblies

“…(D) TEM images of the three samples. TEM image for ESBP3 is reprinted (no changes) from Dodd-o et al, Nat Commun 15 , 1142 (2024), 15 under the Creative Commons CC license ( ). (E) Average thioflavin T fluorescence intensity for the three samples.…”

“…Solutions were then ultracentrifuged for 30 min into Bruker 3.2 mm NMR rotors at 4 °C and 150,000 RCF with ultraclear tubes in an SW-41 Ti swinging bucket rotor fitted onto a Beckman Optima XPN-100 centrifuge. 13 C cross-polarization magic angle spinning (CPMAS) spectra were collected on an 11.75 T magnet (500 MHz, 1 H NMR frequency) with a 3.2 mm Bruker Low-E 1 H/ 13 C/ 15 N NMR probe in a Bruker spectrometer. A 10 kHz magic angle spinning speed was used for all samples.…”

“…Table lists all of the peptides studied in this article. We evaluated the differences in the nanofiber structure formed by the following self-assembling peptides conjugated with the bioactive peptide mimics: (1) the vascular endothelial growth factor (VEGF-A) bioactive mimic that provides a scaffold for angiogenesis, − (2) the insulin-like growth factor (IGF-1) mimic that has several functions including downstream signaling and proliferation of somatic cells, − and (3) SBP3, a mutated ACE2 receptor binding domain fragment, which binds (data not shown) to the spike protein of the SARS-Cov2-RBD-bound ACE2 complex. − The efficacy of these systems from in vivo and in vitro studies, as well as the rational design of the bioactive peptide mimics, is reported elsewhere. ,, By applying the one-dimensional (1D) solid-state NMR experiment 1 H– 13 C cross-polarization magic angle spinning (CPMAS), we were able to identify the amino acids involved in the nanofiber structure and evaluate the structural order of the peptide samples. We discovered that all three of the hypothesized structural outcomes are possible.…”

“… 12 − 14 The efficacy of these systems from in vivo and in vitro studies, as well as the rational design of the bioactive peptide mimics, is reported elsewhere. 6 , 11 , 15 By applying the one-dimensional (1D) solid-state NMR experiment 1 H– 13 C cross-polarization magic angle spinning (CPMAS), we were able to identify the amino acids involved in the nanofiber structure and evaluate the structural order of the peptide samples. We discovered that all three of the hypothesized structural outcomes are possible.…”