FfAME:org :: Elisa Biondi's Publications

Elisa Biondi's Publications

Functional Selection of Tau Oligomerization-Inhibiting Aptamers
Bang Wang, Xiaoshu Pan, I-Ting Teng, Xiaowei Li, Firas Kobeissy, Zo-Yu Wu, Jiepei Zhu, Guangzheng Cai, He Yan, Xin Yan, Mingwei Liang, Fahong Yu, Zunyi Yang, Elisa Biondi, William Haskins, Y. Charles Cao, Steven A. Benner, Weihong Tan, Kevin Wang
Angew. Chem. Int. Ed. (2024) e202402007, https://doi.org/10.1002/anie.202402007
<Abstract>

Pathological hyperphosphorylation and aggregation of microtubule-associated Tau protein contribute to Alzheimer's Disease (AD) and other related tauopathies. Currently, no cure exists for Alzheimer's Disease. Aptamers offer significant potential as next-generation therapeutics in biotechnology and the treatment of neurological disorders. Traditional aptamer selection methods for Tau protein focus on binding affinity rather than interference with pathological Tau. In this study, we developed a new selection strategy to enrich DNA aptamers that bind to surviving monomeric Tau protein under conditions that would typically promote Tau aggregation. Employing this approach, we identified a set of aptamer candidates. Notably, BW1c demonstrates a high binding affinity (Kd = 6.6 nM) to Tau protein and effectively inhibits arachidonic acid (AA)-induced Tau protein oligomerization and aggregation. Additionally, it inhibits GSK3β-mediated Tau hyperphosphorylation in cell-free systems and okadaic acid-mediated Tau hyperphosphorylation in cellular milieu. Lastly, retro-orbital injection of BW1c tau aptamer shows the ability to cross the blood brain barrier and gain access to neuronal cell body. Through further refinement and development, these Tau aptamers may pave the way for a first-in-class neurotherapeutic to mitigate tauopathy-associated neurodegenerative disorders.

Mist and replication
Rajamani, S., Biondi, E.
Nature Physics, Springer (2022) https://doi.org/10.1038/s41567-022-01549-4
<Abstract>

The transition from chemistry to evolvable molecular systems is at the core of origins of life studies. Now, the acidic dew–liquid water dynamic cycling inside simulated Hadean rock pores is found to possibly provide a confined environment for strand separation, replication, mutation, and the evolution of nucleic acids.

Catalytic Synthesis of Polyribonucleic Acid on Prebiotic Rock Glasses
Craig A. Jerome, Hyo-Joong Kim, Stephen J. Mojzsis, Steven A. Benner, and Elisa Biondi
Astrobiology (2022) http://doi.org/10.1089/ast.2022.0027
<Abstract>

Reported here are experiments that show that ribonucleoside triphosphates are converted to polyribonucleic acid when incubated with rock glasses similar to those likely present 4.3-4.4 billion years ago on the Hadean Earth surface, where they were formed by impacts and volcanism. This polyribonucleic acid averages 100-300 nucleotides in length, with a substantial fraction of 3',-5'-dinucleotide linkages. Chemical analyses, including classical methods that were used to prove the structure of natural RNA, establish a polyribonucleic acid structure for these products. The polyribonucleic acid accumulated and was stable for months, with a synthesis rate of 2 x 10^-3 pmoles of triphosphate polymerized each hour per gram of glass (25°C, pH 7.5). These results suggest that polyribonucleotides were available to Hadean environments if triphosphates were. As many proposals are emerging describing how triphosphates might have been made on the Hadean Earth, the process observed here offers an important missing step in models for the prebiotic synthesis of RNA.

In vitro evolution of ribonucleases from expanded genetic alphabets
Jerome, C.A; Hoshika, S.; Bradley, K.M.; Benner, S.A.; Biondi, E.
Proc. Natl. Acad. Sci. USA (2022) 119(44). DOI: 10.1073/pnas.2208261119
<Abstract>

The ability of nucleic acids to catalyze reactions (as well as store and transmit information) is important for both basic and applied science, the first in the context of molecular evolution and the origin of life and the second for biomedical applications. However, the catalytic power of standard nucleic acids (NAs) assembled from just four nucleotide building blocks is limited when compared with that of proteins. Here, we assess the evolutionary potential of libraries of nucleic acids with six nucleotide building blocks as reservoirs for catalysis. We compare the outcomes of in vitro selection experiments toward RNA-cleavage activity of two nucleic acid libraries: one built from the standard four independently replicable nucleotides and the other from six, with the two added nucleotides coming from an artificially expanded genetic information system (AEGIS). Results from comparative experiments suggest that DNA libraries with increased chemical diversity, higher information density, and larger searchable sequence spaces are one order of magnitude richer reservoirs of molecules that catalyze the cleavage of a phosphodiester bond in RNA than DNA libraries built from a standard four-nucleotide alphabet. Evolved AEGISzymes with nitro-carrying nucleobase Z appear to exploit a general acid–base catalytic mechanism to cleave that bond, analogous to the mechanism of the ribonuclease A family of protein enzymes and heavily modified DNAzymes. The AEGISzyme described here represents a new type of catalysts evolved from libraries built from expanded genetic alphabets.

When Did Life Likely Emerge on Earth in an RNA-First Process?
S. A. Benner, E. A. Bell, E. Biondi, R. Brasser, T. Carell, H.-J. Kim, S. J. Mojzsis, A. Omran, M. A. Pasek, D. Trail
ChemSystemsChem2, Chemistry Europe (2020) e1900035
<Abstract>

The widespread presence of ribonucleic acid (RNA) catalysts and cofactors in the Earth's biosphere today suggests that RNA was the first biopolymer to support Darwinian evolution. However, most "path-hypotheses" to generate building blocks for RNA require reduced nitrogen-containing compounds not made in useful amounts in the CO2-N2-H2O atmospheres of the Hadean. We review models for Earth's impact history that invoke a single ~1023 kg impactor (Moneta) to account for measured amounts of platinum, gold, and other siderophilic ("iron-loving") elements on the Earth and Moon. If it were the last sterilizing impactor, by reducing the atmosphere but not the mantle Moneta, would have opened a "window of opportunity" for RNA synthesis, a period when RNA precursors rained from the atmosphere onto land holding oxidized minerals that stabilize advanced RNA precursors and RNA. Surprisingly, this combination of physics, geology, and chemistry suggests a time when RNA formation was most probable, ~120±100 million years after Moneta's impact, or ~4.36±0.1 billion years ago. Uncertainties in this time are driven by uncertainties in rates of productive atmosphere loss and amounts of sub-aerial land.

Chemical guidance in the search for past and extant life on Mars. Decadal Survey in Planetary Sciences and Astrobiology
Benner, S. A., Biondi, E., Kim, H.-J., Spacek, J.
Bulletin of the AAS, AAS (2020) 53(4), DOI:10.3847/25c2cfeb.266df7e7
<Abstract>

NASA should design missions to Mars to generate "Aha!" jolts for scientists researching the molecular origins of life. Recent advances allow these missions to be informed via privileged chemistry that likely generated RNA prebiotically on Earth, as well as general rules that constrain the structure of genetic molecules of extant life on Mars.

Prebiotic Chemistry that Could Not Not Have Happened
Benner S.A., Kim H.-J., and Biondi E.
Life9(4), MDPI 84 (2019) https://doi.org/10.3390/life9040084
<Abstract>

We present a direct route by which RNA might have emerged in the Hadean from a fayalite-magnetite mantle, volcanic SO2 gas, and well-accepted processes that must have created substantial amounts of HCHO and catalytic amounts of glycolaldehyde in the Hadean atmosphere. In chemistry that could not not have happened, these would have generated stable bisulfite addition products that must have rained to the surface, where they unavoidably would have slowly released reactive species that generated higher carbohydrates. The formation of higher carbohydrates is self-limited by bisulfite formation, while borate minerals may have controlled aldol reactions that occurred on any semi-arid surface to capture that precipitation. All of these processes have well-studied laboratory correlates. Further, any semi-arid land with phosphate should have had phosphate anhydrides that, with NH3, gave carbohydrate derivatives that directly react with nucleobases to form the canonical nucleosides. These are phosphorylated by magnesium borophosphate minerals (e.g., luneburgite) and/or trimetaphosphate-borate with Ni2+ catalysis to give nucleoside 5'-diphosphates, which oligomerize to RNA via a variety of mechanisms. The reduced precursors that are required to form the nucleobases came, in this path-hypothesis, from one or more mid-sized (1023-1020 kg) impactors that almost certainly arrived after the Moon-forming event. Their iron metal content almost certainly generated ammonia, nucleobase precursors, and other reduced species in the Hadean atmosphere after it transiently placed the atmosphere out of redox equilibrium with the mantle. In addition to the inevitability of steps in this path-hypothesis on a Hadean Earth if it had semi-arid land, these processes may also have occurred on Mars. Adapted from a lecture by the Corresponding Author at the All-Russia Science Festival at the Lomonosov Moscow State University on 12 October 2019, and is an outcome of a three year project supported by the John Templeton Foundation and the NASA Astrobiology program. Dedicated to David Deamer, on the occasion of his 80th Birthday.

Artificially Expanded Genetic Information Systems for New Aptamer Technologies
Elisa Biondi and Steven A. Benner
Biomedicines, MDPI (2018) 6, 53; doi:10.3390/biomedicines6020053
<Abstract>

Directed evolution was first applied to diverse libraries of DNA and RNA molecules a quarter century ago in the hope of gaining technology that would allow the creation of receptors, ligands, and catalysts on demand. Despite isolated successes, the outputs of this technology have been somewhat disappointing, perhaps because the four building blocks of standard DNA and RNA have too little functionality to have versatile binding properties, and offer too little information density to fold unambiguously. This review covers the recent literature that seeks to create an improved platform to support laboratory Darwinism, one based on an artificially expanded genetic information system (AEGIS) that adds independently replicating nucleotide "letters" to the evolving "alphabet".

Mineral-Organic Interactions in Prebiotic Synthesis. The Discontinuous Synthesis Model for the Formation of RNA in Naturally Complex Geological Environments.
Steven A. Benner, Hyo-Joong Kim, and Elisa Biondi
Nucl. Acids & Mol. Bio.35, Springer 31-83 (2018) https://doi.org/10.1007/978-3-319-93584-3_3
<Abstract>

A common criticism of "prebiotic chemistry research" is that it is done with starting materials that are too pure, in experiments that are too directed, to get results that are too scripted, under conditions that could never have existed on Earth. Planetary scientists in particular remark that these experiments often arise simply because a chemist has a "cool idea" and then pursues it without considering external factors, especially geological and planetary context. A growing literature addresses this criticism and is reviewed here. We assume a model where RNA emerged spontaneously from a prebiotic environment on early Earth, giving the planet its first access to Darwinism. This "RNA First Hypothesis" is not driven by the intrinsic prebiotic accessibility; quite the contrary, RNA is a "prebiotic chemist's nightmare." However, by assuming models for the accretion of the Earth, the formation of the Moon, and the acquisition of Earth's "late veneer," a reasonable geological model can be envisioned to deliver the organic precursors needed to form the nucleobases and ribose of RNA. A geological model having an environment with dry arid land under a carbon dioxide atmosphere receiving effluent from serpentinizing igneous rocks allows their conversion to nucleosides and nucleoside phosphates. Mineral elements including boron and molybdenum prevent organic material from devolving to form "tars" along the way. And dehydration and activation allows the formation of oligomeric RNA that can be stabilized by adsorption on available minerals.

Adsorption of RNA on mineral surfaces and mineral precipitates
Elisa Biondi, Yoshihiro Furukawa, Jun Kawai, and Steven A. Benner
Beilstein J. Org. Chem., Beilstein Institute (2017) 13, 393-404
<Abstract>

The prebiotic significance of laboratory experiments that study the interactions between oligomeric RNA and mineral species is difficult to know. Natural exemplars of specific minerals can differ widely depending on their provenance. While laboratory-generated samples of synthetic minerals can have controlled compositions, they are often viewed as "unnatural". Here, we show how trends in the interaction of RNA with natural mineral specimens, synthetic mineral specimens, and co-precipitated pairs of synthetic minerals, can make a persuasive case that the observed interactions reflect the composition of the minerals themselves, rather than their being simply examples of large molecules associating nonspecifically with large surfaces. Using this approach, we have discovered Periodic Table trends in the binding of oligomeric RNA to alkaline earth carbonate minerals and alkaline earth sulfate minerals, where those trends are the same when measured in natural and synthetic minerals. They are also validated by comparison of co-precipitated synthetic minerals. We also show differential binding of RNA to polymorphic forms of calcium carbonate, and the stabilization of bound RNA on aragonite. These have relevance to the prebiotic stabilization of RNA, where such carbonate minerals are expected to have been abundant, as they appear to be today on Mars.

Laboratory evolution of artificially expanded DNA gives redesignable aptamers that target the toxic form of anthrax protective antigen
Biondi E, Lane JD, Das D, Dasgupta S, Piccirilli JA, Hoshika S, Bradley KM, Krantz BA, Benner SA
Nucl. Acids Res. (2016) Oct 3. pii: gkw890. PubMed PMID: 27701076
<Abstract>

Reported here is a laboratory in vitro evolution (LIVE) experiment based on an artificially expanded genetic information system (AEGIS). This experiment delivers the first example of an AEGIS aptamer that binds to an isolated protein target, the first whose structural contact with its target has been outlined and the first to inhibit biologically important activities of its target, the protective antigen from Bacillus anthracis. We show how rational design based on secondary structure predictions can also direct the use of AEGIS to improve the stability and binding of the aptamer to its target. The final aptamer has a dissociation constant of ~35 nM. These results illustrate the value of AEGIS-LIVE for those seeking to obtain receptors and ligands without the complexities of medicinal chemistry, and also challenge the biophysical community to develop new tools to analyze the spectroscopic signatures of new DNA folds that will emerge in synthetic genetic systems replacing standard DNA and RNA as platforms for LIVE.

Opal Absorbs and Stabilizes RNA - A Hierarchy of Prebiotic Silica Minerals
Biondi, E.; Howell, L.; Benner, S.A.
SynLett (2016) 27, A-E
<Abstract>

A widely held 'RNA first' model proposes that RNA gave organic matter on Earth its first access to Darwinism. Such a proposal, which requires a mechanism to generate RNA from a prebiotic 'soup', must also manage the intrinsic instability of any RNA so formed. Here, we show that silicon dioxide (silica, SiO2), in the form of synthetic opal, adsorbs and stabilizes RNA from aqueous solution. The extent of absorption on fully amorphous silica is less, as is the extent of adsorption on the surface of crystalline quartz. We show that the RNA adsorbed on opal is considerably more stable than the same RNA molecule free in aqueous solution at pH 9.5. This provides a mechanism by which any RNA formed in a prebiotic environment could have been concentrated and stabilized so that it could have later participated in the first Darwinian biology.

RNA structural analysis by enzymatic digestion
Biondi E., Burke D.H.
Methods Mol Biol, Springer (2014) 1086:41-52

Potent Inhibition of HIV-1 Reverse Transcriptase and Replication by Nonpseudoknot, "UCAA-motif" RNA Aptamers
Whatley A.S., Ditzler M.A., Lange M.J., Biondi E., Sawyer A.W., Chang J.L., Franken J.D., Burke D.H.
Mol Ther Nucleic Acids, Nature (2013) 2:e71

Lewis acid catalysis of phosphoryl transfer from a copper(II)-NTP complex in a kinase ribozyme
Biondi E., Poudyal R.R., Forgy J.C., Sawyer A.W., Maxwell A.W., Burke D.H
Nucl. Acids Res. (2013) 41(5):3327-38

A small ribozyme with dual-site kinase activity
Biondi E., Maxwell A.W.R., and Burke D.H.
Nucl. Acids Res. (2012) 40(15):7528-40

Separating and analyzing sulfur-containing RNAs with organomercury gels
Biondi E, Burke DH.
Methods Mol Biol, Springer (2012) 2012;883:111-20
<Abstract>

Polyacrylamide gel electrophoresis is a widely used technique for RNA analysis and purification. The polyacrylamide matrix is highly versatile for chemical derivitization, enabling facile exploitation of thio-mercury chemistry without the need of tedious manipulations and/or expensive coupling reagents, which often give low yields and side products. Here, we describe the use of [(N-acryloylamino)phenyl]mercuric chloride in three-layered polyacrylamide gels to detect, separate, quantify, and analyze sulfur-containing RNAs.

Convergent donor and acceptor substrate utilization among kinase ribozymes
Biondi E., Nickens D.G., Warren S., Saran D., and Burke D.H.
Nucl. Acids Res. (2010) 38(19):6785-95

Montmorillonite protection of an UV-irradiated hairpin ribozyme. Evolution of the RNA world in a mineral environment
Biondi E., Branciamore S., Maurel M.-C., and Gallori E.
BMC Evol. Biol. (2007) 7(Suppl 2):S2

Catalytic activity of hammerhead ribozymes in a clay mineral environment: implications for the RNA World
Biondi E., Branciamore S., Fusi L., Gago, and Gallori E.
Gene (2007) 389:10-18

Looking for the primordial genetic honeycomb
Gallori E., Biondi E., and Branciamore S.
Orig. Life Evol. Biosph., Springer (2006) 36:493-499

Mineral Surfaces as a Cradle of Primordial Genetic Material
Gallori E, Biondi E, Franchi M
Life in the Universe, ed. Seckbach J, Chela-Flores J, Owen T, Raulin F, Netherlands: Springer 145-148 (2004)
<Abstract>

Molecules which store genetic information (DNA and RNA) are central to all life on Earth. The formation of these complex macromolecules, and ultimately life, required specific conditions, including the synthesis and polymerization of precursors (nucleotides), the protection and persistence of information polymers in a changing environment, and the expression of the "biological potential" of the molecules, i.e. their capacity to multiply and evolve. Determining how these steps occurred and how the earliest genetic molecules originated on Earth is a problem that is far from being resolved. Recent observations on the synthesis of polynucleotides on clay surfaces, the resistance of clay-adsorbed nucleic acid molecules to environmental degradation and the biological activity of clay-adsorbed DNA and RNA molecules suggest that mineral surfaces could have played a crucial role in the prebiotic formation of the biomolecules basic to life.