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TitleComputational design and engineering of self-assembling multivalent microproteins with therapeutic potential against SARS-CoV-2.
Journal, issue, pagesJ Nanobiotechnology, Vol. 22, Issue 1, Page 58, Year 2024
Publish dateFeb 10, 2024
AuthorsQin Qin / Xinyi Jiang / Liyun Huo / Jiaqiang Qian / Hongyuan Yu / Haixia Zhu / Wenhao Du / Yuhui Cao / Xing Zhang / Qiang Huang /
PubMed AbstractMultivalent drugs targeting homo-oligomeric viral surface proteins, such as the SARS-CoV-2 trimeric spike (S) protein, have the potential to elicit more potent and broad-spectrum therapeutic ...Multivalent drugs targeting homo-oligomeric viral surface proteins, such as the SARS-CoV-2 trimeric spike (S) protein, have the potential to elicit more potent and broad-spectrum therapeutic responses than monovalent drugs by synergistically engaging multiple binding sites on viral targets. However, rational design and engineering of nanoscale multivalent protein drugs are still lacking. Here, we developed a computational approach to engineer self-assembling trivalent microproteins that simultaneously bind to the three receptor binding domains (RBDs) of the S protein. This approach involves four steps: structure-guided linker design, molecular simulation evaluation of self-assembly, experimental validation of self-assembly state, and functional testing. Using this approach, we first designed trivalent constructs of the microprotein miniACE2 (MP) with different trimerization scaffolds and linkers, and found that one of the constructs (MP-5ff) showed high trimerization efficiency, good conformational homogeneity, and strong antiviral neutralizing activity. With its trimerization unit (5ff), we then engineered a trivalent nanobody (Tr67) that exhibited potent and broad neutralizing activity against the dominant Omicron variants, including XBB.1 and XBB.1.5. Cryo-EM complex structure confirmed that Tr67 stably binds to all three RBDs of the Omicron S protein in a synergistic form, locking them in the "3-RBD-up" conformation that could block human receptor (ACE2) binding and potentially facilitate immune clearance. Therefore, our approach provides an effective strategy for engineering potent protein drugs against SARS-CoV-2 and other deadly coronaviruses.
External linksJ Nanobiotechnology / PubMed:38341574 / PubMed Central
MethodsEM (single particle)
Resolution9.0 Å
Structure data

EMDB-36850: SARS-CoV-2 Omicron BA.1 spike protein in complex with a self-assembling trivalent nanobody Tr67
Method: EM (single particle) / Resolution: 9.0 Å

Source
  • Severe acute respiratory syndrome coronavirus 2
  • synthetic construct (others)

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