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(12) Patent Application Publication (10) Pub. No.: US 2017/0058007 A1 Cox Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2017/0058007 A1 Cox Et Al US 2017005.8007A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0058007 A1 Cox et al. (43) Pub. Date: Mar. 2, 2017 (54) SELF-ASSEMBLED BETASOLENOID (86). PCT No.: PCT/US 15/12934 PROTEIN SCAFFOLDS S 371 (c)(1), (2) Date: Jul. 14, 2016 (71) Applicant: THE REGENTS OF THE Related U.S. Application Data UNIVERSITY OF CALIFORNIA, Oakland, CA (US) (60) Provisional application No. 61/931,485, filed on Jan. 24, 2014. (72) Inventors: Daniel Cox, Oakland, CA (US); Publication Classification Gang-Yu Liu, Oakland, CA (US); (51) Int. Cl. Michael Toney, Oakland, CA (US); Xi C07K I4/435 (2006.01) Chen, Oakland, CA (US); Josh Hihath, C07K I4/45 (2006.01) Oakland, CA (US); Gergely Zimanyi, (52) U.S. Cl. Oakland, CA (US); Natha Robert CPC ...... C07K 14/43563 (2013.01); C07K 14/415 Hayre, Oakland, CA (US); Maria (2013.01) Peralta, Oakland, CA (US) (57) ABSTRACT The present invention provides amyloid fibrils comprising a (21) Appl. No.: 15/111,687 plurality of modified f solenoid protein (mEBSP) monomers. The mBSP monomers are modified to enhance self-assem (22) PCT Filed: Jan. 26, 2015 bly and are useful in a variety of applications. Patent Application Publication Mar. 2, 2017 Sheet 1 of 12 US 2017/0058007 A1 Nanoparticle binding a peptides six. r KY 3 YmXrm marrmyrmor-m-m-m-m-m-m-m-m-m-m-m-m8 Nanoparticle soxas D 's ^ s Substrate birding gi'Olips Substrate Fi. i. Patent Application Publication Mar. 2, 2017. Sheet 2 of 12 US 2017/0058007 A1 SY 3. 38 3. R&AF s V8N SBAFP ri. 2 Patent Application Publication Mar. 2, 2017 Sheet 3 of 12 US 2017/0058007 A1 fr. 3 Patent Application Publication Mar. 2, 2017. Sheet 4 of 12 US 2017/0058007 A1 $»§§§§§ *¿?????? y Patent Application Publication Mar. 2, 2017. 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Sheet 12 of 12 US 2017/0058007 A1 tire is G. 2 US 2017/005.8007 A1 Mar. 2, 2017 SELF-ASSEMBLED BETA SOLENOD designed structure is difficult as the product is at the mercy PROTEIN SCAFFOLDS of viral scaffold. Hence, precise, programmable nanometer scale ordered heterogeneity, as achieved with DNA, is not CROSS-REFERENCES TO RELATED feasible. APPLICATIONS 0007 Amyloid fibrils are self-assembled one-dimen 0001. This application claims benefit under 35 U.S.C. sional protein arrays with fi-Strands perpendicular to the S119(e) to U.S. Application No. 61/931,485, filed Jan. 24, linear axis. They arise both in unregulated self-assembly in 2014 the contents of which are incorporated herein by numerous diseases including Alzheimer's disease and type II reference. diabetes, as well as in regulated contexts in biofilm extra cellular matrices," synapse formation," and hormone res STATEMENT AS TO RIGHTS TO INVENTIONS ervoir manufacture." These fibrils have bending and twist MADE UNDER FEDERALLY SPONSORED ing persistence lengths on the micron scale,' ' which RESEARCH AND DEVELOPMENT contribute to the remarkable tensile strength of spider silk'' and the structural stability of barnacle cement." They have 0002 This work was supported by grants from the previously been used to template metallic nanowire growth, National Science Foundation (DMR-1207624 and DMR ''' and have been used to produce mechanically strong 0844115). The US Government may have certain rights in oriented films.’ this invention. 0008 Amyloid structures are remarkably robust. Gener ally, they can survive heating to the boiling point of water FIELD OF THE INVENTION 25 although there is monomer size and sequence dependence 0003. The present invention relates to amyloid fibers to this result. They are resistant to protease degradation 7 prepared from modified B solenoid protein monomers. The and UV light exposure. To date, amyloids have not been monomers are used for binding nanoparticles and other assembled to produce a significant level of transverse order, functional entities in a variety of applications. nor have they been used to template material growth other than the examples given above. There is also little system BACKGROUND OF THE INVENTION atic understanding of amyloid structure because the lack of 0004 An important goal of nanotechnology is bottom-up transverse order makes it difficult for X-ray diffraction to manufacturing of useful devices and materials via self reveal more than the generic cross f-stacking, although in assembly at room temperature in environmentally benign some instances additional scattering rings in fiber diffraction Solvents. Living systems provide numerous examples of have provided information about transverse dimensions of Such self-assembly in the guise, for example, of protein fibrils and longer periodicity repeats along the fiber axis.’ structures such as microtubules, viral capsids, bacterial S-layers, and amyloid fibrils" in which proteins grow in BRIEF SUMMARY OF THE INVENTION one-dimensional filaments with B-strands perpendicular to 0009. The present invention provides amyloid fibrils the growth axis. comprising a plurality of modified B Solenoid protein 0005. The programmable design of DNA-based nano (mBSP) monomers. The monomers may be derived from a structured scaffolds is extraordinary, allowing for the tem variety of sources, such as antifreeze proteins. The mBSP plating of ordered heterogeneous arrays of, e.g., metallic monomers are modified to enhance self-assembly, by for nanoparticles, proteins, and semiconducting wires. How example, removing an end cap that prevents amyloid aggre ever, it is plagued with technical barriers to advancement, gation. The mBSPs may also be modified to include at least including: a) difficulties in Scaling it to industrial applica one amino acid residue that promotes attachment of the fibril tions, b) high error rates of DNA replication, c) denaturation to a solid Support, a nanoparticle, a biological molecule (e.g., of DNA scaffolds/bundles at moderate temperatures (-60° an enzyme), a bacterial or eukaryotic cell (in which case the C.), and d) loss of integrity under exposure to ultraviolet scaffold can be used a matrix for tissue growth), or addi light and enzymes, e) very limited capability to carry a tional amyloid fibrils. broad range of functional groups: f) limited tenability in 0010. The invention also provides method of forming a terms of ternary and quaternary structures. nanomaterial. The methods comprise (a) contacting a plu 0006 Belcher and collaborators have used the M13 virus rality of nanoparticles with a scaffold comprising at least one as a scaffold for self-assembly of a wide variety of inorganic amyloid fibril comprising a plurality of modified B solenoid materials. Their strategy relies on modifying coat proteins protein (mBSP) monomers; and (b) fusing the nanoparticles with peptides that are selected through phage display for to form the nanomaterial. The methods may further com templating a specific material." In one example, the M13 prise the step of attaching the scaffold to a solid Support prior major coat protein was coated by a peptide with FePO to the step of contacting the plurality of nanoparticles with nanoparticle templating activity while the attachment pro the mBSP scaffold. The nature of the nanoparticles is not teins at the end of the virus were fused to a peptide known critical to the invention and can be selected based on the to adhere to carbon nanotubes.' Incubation of the virus with desired function to be achieved. iron and phosphate ions together with single-walled carbon 0011. The invention further provides scaffolds compris nanotubes generated a self-assembled working cathode. ing at least one amyloid fibril of the invention. The scaffold However, the M13 approach is limited by several factors: (a) is typically bound to a plurality of nanoparticles. viruses are large (M13 is nearly a micron in length); (b) templating sites are limited to the coat proteins, and the geometry is restricted to that provided by the virus; (c) while DEFINITIONS the viruses can order as liquid crystals, the ordering is on the (0012. The term “B-solenoid protein” (BSP) refers to micron scale; and (d) the capability to engineer or program proteins having backbones that turn helically in either a left US 2017/005.8007 A1 Mar. 2, 2017 or right-handed sense around the long axis of the protein threonine bonding, disulfide bridges, or metal mediated from the N-terminus to the C-terminus to form B-sheets, and chelation of histidine side chains can also be used. One of have regular geometric structures (triangles, rectangles, etc.) skill will recognize that by adjusting the side chain struc with 1.5-2 nm sides. The wild type (WT) BSPs are inhibited tures on different faces of mBSPs, programmable lateral from amyloid aggregation (end-to-end polymerization to assembly that can allow specific geometric arrangement of give cross B-fibrils) by natural capping features and/or the BSP scaffold can be achieved. Modifications of external structural irregularities on one or both ends.
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