Imperial College London

Dr Francesco A. Aprile

Faculty of Natural SciencesDepartment of Chemistry

Future Leadership Fellow
 
 
 
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Contact

 

+44 (0)20 7594 5545f.aprile Website

 
 
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Location

 

110FMolecular Sciences Research HubWhite City Campus

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Summary

 

Publications

Publication Type
Year
to

43 results found

Heller GT, Aprile FA, Michaels TCT, Limbocker R, Perni M, Ruggeri FS, Mannini B, Löhr T, Bonomi M, Camilloni C, De Simone A, Felli IC, Pierattelli R, Knowles TPJ, Dobson CM, Vendruscolo Met al., 2020, Small-molecule sequestration of amyloid-β as a drug discovery strategy for Alzheimer's disease., Sci Adv, Vol: 6

Disordered proteins are challenging therapeutic targets, and no drug is currently in clinical use that modifies the properties of their monomeric states. Here, we identify a small molecule (10074-G5) capable of binding and sequestering the intrinsically disordered amyloid-β (Aβ) peptide in its monomeric, soluble state. Our analysis reveals that this compound interacts with Aβ and inhibits both the primary and secondary nucleation pathways in its aggregation process. We characterize this interaction using biophysical experiments and integrative structural ensemble determination methods. We observe that this molecule increases the conformational entropy of monomeric Aβ while decreasing its hydrophobic surface area. We also show that it rescues a Caenorhabditis elegans model of Aβ-associated toxicity, consistent with the mechanism of action identified from the in silico and in vitro studies. These results illustrate the strategy of stabilizing the monomeric states of disordered proteins with small molecules to alter their behavior for therapeutic purposes.

Journal article

Ikenoue T, Aprile FA, Sormanni P, Ruggeri FS, Perni M, Heller GT, Haas CP, Middel C, Limbocker R, Mannini B, Michaels TCT, Knowles TPJ, Dobson CM, Vendruscolo Met al., 2020, A rationally designed bicyclic peptide remodels Aβ42 aggregation in vitro and reduces its toxicity in a worm model of Alzheimer's disease., Sci Rep, Vol: 10

Bicyclic peptides have great therapeutic potential since they can bridge the gap between small molecules and antibodies by combining a low molecular weight of about 2 kDa with an antibody-like binding specificity. Here we apply a recently developed in silico rational design strategy to produce a bicyclic peptide to target the C-terminal region (residues 31-42) of the 42-residue form of the amyloid β peptide (Aβ42), a protein fragment whose aggregation into amyloid plaques is linked with Alzheimer's disease. We show that this bicyclic peptide is able to remodel the aggregation process of Aβ42 in vitro and to reduce its associated toxicity in vivo in a C. elegans worm model expressing Aβ42. These results provide an initial example of a computational approach to design bicyclic peptides to target specific epitopes on disordered proteins.

Journal article

Aprile FA, Sormanni P, Podpolny M, Chhangur S, Needham L-M, Ruggeri FS, Perni M, Limbocker R, Heller GT, Sneideris T, Scheidt T, Mannini B, Habchi J, Lee SF, Salinas PC, Knowles TPJ, Dobson CM, Vendruscolo Met al., 2020, Rational design of a conformation-specific antibody for the quantification of A beta oligomers, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 117, Pages: 13509-13518, ISSN: 0027-8424

Journal article

Limbocker R, Mannini B, Cataldi R, Chhangur S, Wright AK, Kreiser RP, Albright JA, Chia S, Habchi J, Sormanni P, Kumita JR, Ruggeri FS, Dobson CM, Chiti F, Aprile FA, Vendruscolo Met al., 2020, Rationally Designed Antibodies as Research Tools to Study the Structure-Toxicity Relationship of Amyloid-beta Oligomers, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol: 21

Journal article

Faravelli G, Raimondi S, Marchese L, Partridge FA, Soria C, Mangione PP, Canetti D, Perni M, Aprile FA, Zorzoli I, Di Schiavi E, Lomas DA, Bellotti V, Sattelle DB, Giorgetti Set al., 2019, C. elegans expressing D76N β2-microglobulin: a model for in vivo screening of drug candidates targeting amyloidosis., Sci Rep, Vol: 9

The availability of a genetic model organism with which to study key molecular events underlying amyloidogenesis is crucial for elucidating the mechanism of the disease and the exploration of new therapeutic avenues. The natural human variant of β2-microglobulin (D76N β2-m) is associated with a fatal familial form of systemic amyloidosis. Hitherto, no animal model has been available for studying in vivo the pathogenicity of this protein. We have established a transgenic C. elegans line, expressing the human D76N β2-m variant. Using the INVertebrate Automated Phenotyping Platform (INVAPP) and the algorithm Paragon, we were able to detect growth and motility impairment in D76N β2-m expressing worms. We also demonstrated the specificity of the β2-m variant in determining the pathological phenotype by rescuing the wild type phenotype when β2-m expression was inhibited by RNA interference (RNAi). Using this model, we have confirmed the efficacy of doxycycline, an inhibitor of the aggregation of amyloidogenic proteins, in rescuing the phenotype. In future, this C. elegans model, in conjunction with the INVAPP/Paragon system, offers the prospect of high-throughput chemical screening in the search for new drug candidates.

Journal article

Lindstedt PR, Aprile FA, Matos MJ, Perni M, Bertoldo JB, Bernardim B, Peter Q, Jimenez-Oses G, Knowles TPJ, Dobson CM, Corzana F, Vendruscolo M, Bernardes GJLet al., 2019, Enhancement of the Anti-Aggregation Activity of a Molecular Chaperone Using a Rationally Designed Post-Translational Modification, ACS CENTRAL SCIENCE, Vol: 5, Pages: 1417-1424, ISSN: 2374-7943

Journal article

De S, Whiten DR, Ruggeri FS, Hughes C, Rodrigues M, Sideris D, Taylor CG, Aprile FA, Muyldermans S, Knowles TPJ, Vendruscolo M, Bryant C, Blennow K, Skoog I, Kern S, Zetterberg H, Klenerman Det al., 2019, Soluble aggregates present in cerebrospinal fluid change in size and mechanism of toxicity during Alzheimer's disease progression, ACTA NEUROPATHOLOGICA COMMUNICATIONS, Vol: 7, ISSN: 2051-5960

Journal article

De S, Wirthensohn DC, Flagmeier P, Hughes C, Aprile FA, Ruggeri FS, Whiten DR, Emin D, Xia Z, Varela JA, Sormanni P, Kundel F, Knowles TPJ, Dobson CM, Bryant C, Vendruscolo M, Klenerman Det al., 2019, Different soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanisms., Nat Commun, Vol: 10

Protein aggregation is a complex process resulting in the formation of heterogeneous mixtures of aggregate populations that are closely linked to neurodegenerative conditions, such as Alzheimer's disease. Here, we find that soluble aggregates formed at different stages of the aggregation process of amyloid beta (Aβ42) induce the disruption of lipid bilayers and an inflammatory response to different extents. Further, by using gradient ultracentrifugation assay, we show that the smaller aggregates are those most potent at inducing membrane permeability and most effectively inhibited by antibodies binding to the C-terminal region of Aβ42. By contrast, we find that the larger soluble aggregates are those most effective at causing an inflammatory response in microglia cells and more effectively inhibited by antibodies targeting the N-terminal region of Aβ42. These findings suggest that different toxic mechanisms driven by different soluble aggregated species of Aβ42 may contribute to the onset and progression of Alzheimer's disease.

Journal article

Heller GT, Aprile FA, Bonomi M, Camilloni C, De Simone A, Vendruscolo Met al., 2019, Probing Specificity in Disordered Protein Interactions with Small Molecules using Integrative Methods, 63rd Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 180A-180A, ISSN: 0006-3495

Conference paper

Sormanni P, Aprile FA, Vendruscolo M, 2018, Third generation antibody discovery methods: in silico rational design, CHEMICAL SOCIETY REVIEWS, Vol: 47, Pages: 9137-9157, ISSN: 0306-0012

Journal article

Perni M, Casford S, Aprile FA, Nollen EA, Knowles TPJ, Vendruscolo M, Dobson CMet al., 2018, Automated Behavioral Analysis of Large C. elegans Populations Using a Wide Field-of-view Tracking Platform, JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, ISSN: 1940-087X

Journal article

Giorgetti S, Greco C, Tortora P, Aprile FAet al., 2018, Targeting Amyloid Aggregation: An Overview of Strategies and Mechanisms, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol: 19

Journal article

Giorgetti S, Greco C, Tortora P, Aprile FAet al., 2018, Targeting Amyloid Aggregation: An Overview of Strategies and Mechanisms

<jats:p>Amyloids result from the aggregation of several unrelated proteins, due to either specific mutations or promoting intra- or extra-cellular conditions. Structurally, they are rich in intermolecular &amp;beta;-sheets and are the causative agents of several diseases, both neurodegenerative and systemic. It is believed that the most toxic species are small aggregates, referred to as oligomers, rather than the final fibrillar assemblies. Their mechanisms of toxicity are mostly mediated by aberrant interactions with the cell membranes, with resulting derangement of membrane-related functions. Much effort is being put in the search for natural antiamyloid agents, and/or in the development of synthetic molecules. Actually, it is well documented that the prevention of amyloid aggregation results in several cytoprotective effects. Here, we portray the state of the art in the field. Several natural compounds are effective antiamyloid agents, notably tetracyclines and polyphenols. They are generally non-specific, as documented by their partially overlapping mechanisms, and the capability to interfere with the aggregation of several unrelated proteins. Among rationally designed molecules, we mention the prominent examples of &amp;beta;-breakers peptides, whole antibodies and fragments thereof, and the special case of drugs contrasting transthyretin aggregation. In this framework, we stress the pivotal role of the computational approaches. When combined with biophysical methods, in several cases they have helped clarify in detail the protein/drug modes of interaction, which make it plausible that more effective drugs will be developed in the future.</jats:p>

Journal article

Perni M, Flagmeier P, Limbocker R, Cascella R, Aprile FA, Galvagnion C, Heller GT, Meisl G, Chen SW, Kumita JR, Challa PK, Kirkegaard JB, Cohen SIA, Mannini B, Barbut D, Nollen EAA, Cecchi C, Cremades N, Knowles TPJ, Chiti F, Zasloff M, Vendruscolo M, Dobson CMet al., 2018, Multistep Inhibition of alpha-Synuclein Aggregation and Toxicity in Vitro and in Vivo by Trodusquemine, ACS CHEMICAL BIOLOGY, Vol: 13, Pages: 2308-2319, ISSN: 1554-8929

Journal article

Wright MA, Aprile FA, Bellaiche MMJ, Michaels TCT, Muller T, Arosio P, Vendruscolo M, Dobson CM, Knowles TPJet al., 2018, Cooperative Assembly of Hsp70 Subdomain Clusters, BIOCHEMISTRY, Vol: 57, Pages: 3641-3649, ISSN: 0006-2960

Journal article

Bongiovanni MN, Aprile FA, Sormanni P, Vendruscolo Met al., 2018, A Rationally Designed Hsp70 Variant Rescues the Aggregation-Associated Toxicity of Human IAPP in Cultured Pancreatic Islet β-Cells., Int J Mol Sci, Vol: 19

Molecular chaperones are key components of the protein homeostasis system against protein misfolding and aggregation. It has been recently shown that these molecules can be rationally modified to have an enhanced activity against specific amyloidogenic substrates. The resulting molecular chaperone variants can be effective inhibitors of protein aggregation in vitro, thus suggesting that they may provide novel opportunities in biomedical and biotechnological applications. Before such opportunities can be exploited, however, their effects on cell viability should be better characterised. Here, we employ a rational design method to specifically enhance the activity of the 70-kDa heat shock protein (Hsp70) against the aggregation of the human islet amyloid polypeptide (hIAPP, also known as amylin). We then show that the Hsp70 variant that we designed (grafted heat shock protein 70 kDa-human islet amyloid polypeptide, GHsp70-hIAPP) is significantly more effective than the wild type in recovering the viability of cultured pancreatic islet &beta;-cells RIN-m5F upon hIAPP aggregation. These results indicate that a full recovery of the toxic effects of hIAPP aggregates on cultured pancreatic cells can be achieved by increasing the specificity and activity of Hsp70 towards hIAPP, thus providing evidence that the strategy presented here provides a possible route for rationally tailoring molecular chaperones for enhancing their effects in a target-dependent manner.

Journal article

Bonanomi M, Roffia V, De Palma A, Lombardi A, Aprile FA, Visentin C, Tortora P, Mauri P, Regonesi MEet al., 2018, The polyglutamine protein ataxin-3 enables normal growth under heat shock conditions in the methylotrophic yeast Pichia pastoris (vol 7, 2017), SCIENTIFIC REPORTS, Vol: 8, ISSN: 2045-2322

Journal article

Perni M, Aprile FA, Casford S, Mannini B, Sormanni P, Dobson CM, Vendruscolo Met al., 2017, Delivery of Native Proteins into C-elegans Using a Transduction Protocol Based on Lipid Vesicles, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322

Journal article

Bonanomi M, Roffia V, De Palma A, Lombardi A, Aprile FA, Visentin C, Tortora P, Mauri P, Regonesi MEet al., 2017, The polyglutamine protein ataxin-3 enables normal growth under heat shock conditions in the methylotrophic yeast Pichia pastoris, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322

Journal article

Bertoldo JB, Rodrigues T, Dunsmore L, Aprile FA, Marques MC, Rosado LA, Boutureira O, Steinbrecher TB, Sherman W, Corzana F, Terenzi H, Bernardes GJLet al., 2017, A Water-Bridged Cysteine-Cysteine Redox Regulation Mechanism in Bacterial Protein Tyrosine Phosphatases, CHEM, Vol: 3, Pages: 665-677, ISSN: 2451-9294

Journal article

Heller GT, Aprilel FA, Bonomi M, Camilloni C, De Simone A, Vendruscolo Met al., 2017, Sequence Specificity in the Entropy-Driven Binding of a Small Molecule and a Disordered Peptide, JOURNAL OF MOLECULAR BIOLOGY, Vol: 429, Pages: 2772-2779, ISSN: 0022-2836

Journal article

Heller GT, Aprile FA, Vendruscolo M, 2017, Methods of probing the interactions between small molecules and disordered proteins, CELLULAR AND MOLECULAR LIFE SCIENCES, Vol: 74, Pages: 3225-3243, ISSN: 1420-682X

Journal article

Aprile FA, Kallstig E, Limorenko G, Vendruscolo M, Ron D, Hansen Cet al., 2017, The molecular chaperones DNAJB6 and Hsp70 cooperate to suppress alpha-synuclein aggregation, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322

Journal article

Aprile FA, Sormanni P, Perni M, Arosio P, Linse S, Knowles TPJ, Dobson CM, Vendruscolo Met al., 2017, Selective targeting of primary and secondary nucleation pathways in A beta 42 aggregation using a rational antibody scanning method, SCIENCE ADVANCES, Vol: 3, ISSN: 2375-2548

Journal article

Sin O, de Jong T, Mata-Cabana A, Kudron M, Zaini MA, Aprile FA, Seinstra RI, Stroo E, Prins RW, Martineau CN, Wang HH, Hogewerf W, Steinhof A, Wanker EE, Vendruscolo M, Calkhoven CF, Reinke V, Guryev V, Nollen EAAet al., 2017, Identification of an RNA Polymerase III Regulator Linked to Disease-Associated Protein Aggregation, MOLECULAR CELL, Vol: 65, Pages: 1096-+, ISSN: 1097-2765

Journal article

Aprile FA, Arosio P, Fusco G, Chen SW, Kumita JR, Dhulesia A, Tortora P, Knowles TPJ, Vendruscolo M, Dobson CM, Cremades Net al., 2017, Inhibition of alpha-Synuclein Fibril Elongation by Hsp70 Is Governed by a Kinetic Binding Competition between alpha-Synuclein Species, BIOCHEMISTRY, Vol: 56, Pages: 1177-1180, ISSN: 0006-2960

Journal article

Perni M, Galvagnion C, Maltsev A, Meisl G, Mueller MBD, Challa PK, Kirkegaard JB, Flagmeier P, Cohen SIA, Cascella R, Chen SW, Limboker R, Sormanni P, Heller GT, Aprile FA, Cremades N, Cecchi C, Chiti F, Nollen EAA, Knowles TPJ, Vendruscolo M, Bax A, Zasloff M, Dobson CMet al., 2017, A natural product inhibits the initiation of alpha-synuclein aggregation and suppresses its toxicity, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 114, Pages: E1009-E1017, ISSN: 0027-8424

Journal article

Borkar AN, Bardaro MF, Camilloni C, Aprile FA, Varani G, Vendruscolo Met al., 2016, Structure of a low-population binding intermediate in protein-RNA recognition, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 113, Pages: 7171-7176, ISSN: 0027-8424

Journal article

Arosio P, Hu K, Aprile FA, Mueller T, Knowles TPJet al., 2016, Microfluidic Diffusion Viscometer for Rapid Analysis of Complex Solutions, ANALYTICAL CHEMISTRY, Vol: 88, Pages: 3488-3493, ISSN: 0003-2700

Journal article

Arosio P, Mueller T, Rajah L, Yates EV, Aprile FA, Zhang Y, Cohen SIA, White DA, Herling TW, De Genst EJ, Linse S, Vendruscolo M, Dobson CM, Knowles TPJet al., 2016, Microfluidic Diffusion Analysis of the Sizes and Interactions of Proteins under Native Solution Conditions, ACS NANO, Vol: 10, Pages: 333-341, ISSN: 1936-0851

Journal article

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