Alessio Ciulli

Last updated
Alessio Ciulli
FRSE FRSC
Born (1977-07-22) 22 July 1977 (age 47)
Florence, Italy
Nationality Italian British
Alma mater University of Florence(laurea), University of Cambridge(PhD)
Scientific career
FieldsTargeted Protein Degradation, Chemical Biology
Institutions University of Dundee
Thesis
Doctoral advisors Chris Abell
Website https://www.lifesci.dundee.ac.uk/people/alessio-ciulli-0; https://www.dundee.ac.uk/cetpd

Alessio Ciulli FRSE FRSC (born in Firenze, 22 July 1977) is an Italian British biochemist. Currently, he is the Professor of Chemical & Structural Biology at the School of Life Sciences, University of Dundee, where he founded and directs Dundee' new Centre for Targeted Protein Degradation (CeTPD). He is also the scientific co-founder and advisor of Amphista Therapeutics. [1]

Contents

Educational background

Alessi Ciulli attended University of Florence in his hometown with an undergraduate laurea in chemistry and graduated magna cum laude. Under the late Prof Ivano Bertini, his final year laurea project was in computational drug design and NMR spectroscopy of matrix metalloproteases. [2] Awarded with a Gates Cambridge Scholarship, he did his PhD under the supervision of the late Professor Chris Abell at the University of Cambridge and in collaboration with Astex Technology ( now Astex Pharmaceuticals ) produced a thesis concerned with studying weak protein-ligand interactions using biophysical and structural methods.

Career

Ciulli remained in Cambridge University to conduct post-doctoral research on fragment-based drug discovery with Professor Abell and Professor Tom L. Blundell, under a College Junior Research Fellowship. Between February and June 2009, Ciulli went to Yale University as Human Frontier Science Programme visiting fellow to visit the laboratory of Professor Craig Crews before returning to Cambridge University to start his independent research career. [3] While at Cambridge, Ciulli was the group leader in the Department of Chemistry, Director of Studies in Chemistry and BBSRC David Phillis Fellow at Christ's College. In April 2013, he took up a Readership in Chemical & Structural Biology as a principal investigator within the Division of Biological Chemistry and Drug Discovery in the University of Dundee. Ciulli was promoted as the Professor of Chemical & Structural Biology in the same division in October 2016. In 2017, he co-founded Amphista Therapeutics, a company that focuses on developing drugs based on targeted protein degradation. [1] He was elected to the Fellowship of the Royal Society of Edinburgh in 2023.

Research

With his team in the Ciulli laboratory, Ciulli's works aim to develop small molecules inducing targeted protein degradation and modulating protein-protein interactions. One example of this type of work is the discovery of proteolysis-targeting chimera or PROTAC and its therapeutic potential. [4] [5] Recruitment of an E3 ligase to the target protein by the PROTAC is a critical step in the mechanism of action, because it triggers the target protein to be ubiquitinated and then degraded by the proteasome. Ciulli and his colleagues were the first to produce an X-ray crystal structure of a class of PROTAC simultaneously bound to the target protein and the E3 ubiquitin ligase. [6] Much of Ciulli's research also contributed to studies on the Von Hippel-Lindau protein E3 ligase, especially in targeting the E3 ligase with small molecules. [7] [8] [9] [10] In general, Ciulli's scientific contributions focus on targeted protein degradation (TPD) as a therapeutic modality in cancer and other diseases. His works on TPD led to the founding of Amphista Therapeutics. Amongst the other scientific accomplishments and discoveries of his laboratory, is the development of a chemical-genetic “bump and hole” approach in which Ciulli and colleagues designed an engineered mutant variant of BET bromodomains able to accommodate selectively its binding ligand, enabling the individual roles of BET proteins to be elucidated.

Awards

Related Research Articles

<span class="mw-page-title-main">Proteasome</span> Protein complexes which degrade ubiquitin-tagged proteins by proteolysis

Proteasomes are protein complexes which degrade ubiquitin-tagged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.

<span class="mw-page-title-main">Ubiquitin</span> Regulatory protein found in most eukaryotic tissues

Ubiquitin is a small regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ubiquitously. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Four genes in the human genome code for ubiquitin: UBB, UBC, UBA52 and RPS27A.

<span class="mw-page-title-main">Ubiquitin ligase</span> Protein

A ubiquitin ligase is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin from the E2 to the protein substrate. In simple and more general terms, the ligase enables movement of ubiquitin from a ubiquitin carrier to another thing by some mechanism. The ubiquitin, once it reaches its destination, ends up being attached by an isopeptide bond to a lysine residue, which is part of the target protein. E3 ligases interact with both the target protein and the E2 enzyme, and so impart substrate specificity to the E2. Commonly, E3s polyubiquitinate their substrate with Lys48-linked chains of ubiquitin, targeting the substrate for destruction by the proteasome. However, many other types of linkages are possible and alter a protein's activity, interactions, or localization. Ubiquitination by E3 ligases regulates diverse areas such as cell trafficking, DNA repair, and signaling and is of profound importance in cell biology. E3 ligases are also key players in cell cycle control, mediating the degradation of cyclins, as well as cyclin dependent kinase inhibitor proteins. The human genome encodes over 600 putative E3 ligases, allowing for tremendous diversity in substrates.

<span class="mw-page-title-main">Von Hippel–Lindau tumor suppressor</span> Mammalian protein found in humans

The Von Hippel–Lindau tumor suppressor also known as pVHL is a protein that, in humans, is encoded by the VHL gene. Mutations of the VHL gene are associated with Von Hippel–Lindau disease, which is characterized by hemangioblastomas of the brain, spinal cord and retina. It is also associated with kidney and pancreatic lesions.

<span class="mw-page-title-main">SCF complex</span>

Skp, Cullin, F-box containing complex is a multi-protein E3 ubiquitin ligase complex that catalyzes the ubiquitination of proteins destined for 26S proteasomal degradation. Along with the anaphase-promoting complex, SCF has important roles in the ubiquitination of proteins involved in the cell cycle. The SCF complex also marks various other cellular proteins for destruction.

Ubiquitin-conjugating enzymes, also known as E2 enzymes and more rarely as ubiquitin-carrier enzymes, perform the second step in the ubiquitination reaction that targets a protein for degradation via the proteasome. The ubiquitination process covalently attaches ubiquitin, a short protein of 76 amino acids, to a lysine residue on the target protein. Once a protein has been tagged with one ubiquitin molecule, additional rounds of ubiquitination form a polyubiquitin chain that is recognized by the proteasome's 19S regulatory particle, triggering the ATP-dependent unfolding of the target protein that allows passage into the proteasome's 20S core particle, where proteases degrade the target into short peptide fragments for recycling by the cell.

<span class="mw-page-title-main">CUL4A</span> Protein-coding gene in humans

Cullin-4A is a protein that in humans is encoded by the CUL4A gene. CUL4A belongs to the cullin family of ubiquitin ligase proteins and is highly homologous to the CUL4B protein. CUL4A regulates numerous key processes such as DNA repair, chromatin remodeling, spermatogenesis, haematopoiesis and the mitotic cell cycle. As a result, CUL4A has been implicated in several cancers and the pathogenesis of certain viruses including HIV. A component of a CUL4A complex, Cereblon, was discovered to be a major target of the teratogenic agent thalidomide.

<span class="mw-page-title-main">CUL4B</span> Protein-coding gene in humans

Cullin-4B is a protein that in humans is encoded by the CUL4B gene which is located on the X chromosome. CUL4B has high sequence similarity with CUL4A, with which it shares certain E3 ubiquitin ligase functions. CUL4B is largely expressed in the nucleus and regulates several key functions including: cell cycle progression, chromatin remodeling and neurological and placental development in mice. In humans, CUL4B has been implicated in X-linked intellectual disability and is frequently mutated in pancreatic adenocarcinomas and a small percentage of various lung cancers. Viruses such as HIV can also co-opt CUL4B-based complexes to promote viral pathogenesis. CUL4B complexes containing Cereblon are also targeted by the teratogenic drug thalidomide.

<span class="mw-page-title-main">CUL3</span> Protein-coding gene in humans

Cullin 3 is a protein that in humans is encoded by the CUL3 gene.

<span class="mw-page-title-main">USP20</span> Protein-coding gene in the species Homo sapiens

Ubiquitin carboxyl-terminal hydrolase 20 is an enzyme that in humans is encoded by the USP20 gene.

<span class="mw-page-title-main">Cereblon</span>

Cereblon is a protein that in humans is encoded by the CRBN gene. The gene that encodes the cereblon protein is found on the human chromosome 3, on the short arm at position p26.3 from base pair 3,190,676 to base pair 3,221,394. CRBN orthologs are highly conserved from plants to humans.

Chemoproteomics entails a broad array of techniques used to identify and interrogate protein-small molecule interactions. Chemoproteomics complements phenotypic drug discovery, a paradigm that aims to discover lead compounds on the basis of alleviating a disease phenotype, as opposed to target-based drug discovery, in which lead compounds are designed to interact with predetermined disease-driving biological targets. As phenotypic drug discovery assays do not provide confirmation of a compound's mechanism of action, chemoproteomics provides valuable follow-up strategies to narrow down potential targets and eventually validate a molecule's mechanism of action. Chemoproteomics also attempts to address the inherent challenge of drug promiscuity in small molecule drug discovery by analyzing protein-small molecule interactions on a proteome-wide scale. A major goal of chemoproteomics is to characterize the interactome of drug candidates to gain insight into mechanisms of off-target toxicity and polypharmacology.

Craig M. Crews is an American scientist at Yale University known for his contributions to chemical biology. He is known for his contributions to the field of induced proximity through his work in creating heterobifunctional molecules that "hijack" cellular processes by inducing the interaction of two proteins inside a living cell. His initial work focused on the discovery of PROteolysis-TArgeting Chimeras (PROTACs) to trigger degradation of disease-causing proteins, a process known as targeted protein degradation (TPD), and he has since developed new versions of -TACs to leverage other cellular processes and protein families to treat disease.

A proteolysis targeting chimera (PROTAC) is a molecule that can remove specific unwanted proteins. Rather than acting as a conventional enzyme inhibitor, a PROTAC works by inducing selective intracellular proteolysis. A heterobifunctional molecule with two active domains and a linker, PROTACs consist of two covalently linked protein-binding molecules: one capable of engaging an E3 ubiquitin ligase, and another that binds to a target protein meant for degradation. Recruitment of the E3 ligase to the target protein results in ubiquitination and subsequent degradation of the target protein via the proteasome. Because PROTACs need only to bind their targets with high selectivity, there are currently many efforts to retool previously ineffective inhibitor molecules as PROTACs for next-generation drugs.

<span class="mw-page-title-main">Helen Walden</span> English structural biologist

Helen Walden is an English structural biologist who received the Colworth medal from the Biochemical Society in 2015. She was awarded European Molecular Biology Organization (EMBO) membership in 2022. She is a Professor of Structural Biology at the University of Glasgow and has made significant contributions to the Ubiquitination field.

<span class="mw-page-title-main">Daniel Nomura</span> American chemical biologist

Daniel K. Nomura is an American chemical biologist and Professor of Chemical Biology and Molecular Therapeutics at the University of California, Berkeley, in the Departments of Chemistry and Molecular & Cell Biology. His work employs chemoproteomic approaches to develop small molecule therapeutics and therapeutic modalities against traditionally "undruggable" proteins.

<span class="mw-page-title-main">Molecular glue</span> Class of chemical compounds

Molecular glue refers to a class of chemical compounds or molecules that play a crucial role in binding and stabilizing protein-protein interactions in biological systems. These molecules act as "glue" by enhancing the affinity between proteins, ultimately influencing various cellular processes. Molecular glue compounds have gained significant attention in the fields of drug discovery, chemical biology, and fundamental research due to their potential to modulate protein interactions, and thus, impact various cellular pathways. They have unlocked avenues in medicine previously thought to be "undruggable".

<span class="mw-page-title-main">Nicolas H. Thomä</span> German structural and chemical biologist

Nicolas H. Thomä is a German researcher, full professor at the EPFL School of Life Sciences and Director of the Paternot Chair for Cancer Research in Lausanne, Switzerland. He is a biochemist and structural biologist and a leading researcher in the fields of ubiquitin ligase biology and DNA repair.

James Allen Wells is a Professor of Pharmaceutical Chemistry and Cellular & Molecular Pharmacology at the University of California, San Francisco (UCSF) and a member of the National Academy of Sciences. He received his B.A. degrees in biochemistry and psychology from University of California, Berkeley in 1973 and a PhD in biochemistry from Washington State University with Ralph Yount, PhD in 1979. He completed his postdoctoral studies at Stanford University School of Medicine with George Stark in 1982. He is a pioneer in protein engineering, phage display, fragment-based lead discovery, cellular apoptosis, and the cell surface proteome.

Chimeric small molecule therapeutics are a class of drugs designed with multiple active domains to operate outside of the typical protein inhibition model. While most small molecule drugs inhibit target proteins by binding their active site, chimerics form protein-protein ternary structures to induce degradation or, less frequently, other protein modifications.

References

  1. 1 2 "Our Foundations". Amphista Therapeutics. Retrieved 2022-03-28.
  2. ↑ Gray, Harry Barkus; Banci, Lucia; Luchinat, Claudio; Turano, Paola (September 2012). "Ivano Bertini 1940–2012" (PDF). Nature Structural & Molecular Biology. 19 (9): 868–869. doi: 10.1038/nsmb.2369 . S2CID   22004688.
  3. ↑ "Alessio Ciulli". ORCID. Retrieved 2022-03-28.
  4. ↑ Scudellari, Megan (20 March 2019). "Protein-slaying drugs could be the next blockbuster therapies". Nature. 567 (7748): 298–300. Bibcode:2019Natur.567..298S. doi: 10.1038/d41586-019-00879-3 . PMID   30894734. S2CID   84186557.
  5. ↑ Zengerle, Michael; Chan, Kwok-Ho; Ciulli, Alessio (21 August 2015). "Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4". ACS Chemical Biology. 10 (8): 1770–1777. doi:10.1021/acschembio.5b00216. PMC   4548256 . PMID   26035625.
  6. ↑ Gadd, Morgan S.; Testa, Andrea; Lucas, Xavier; Chan, Kwok-Ho; Chen, Wenzhang; Lamont, Douglas J.; Zengerle, Michael; Ciulli, Alessio (May 2017). "Structural basis of PROTAC cooperative recognition for selective protein degradation". Nature Chemical Biology. 13 (5): 514–521. doi:10.1038/nchembio.2329. PMC   5392356 . PMID   28288108.
  7. ↑ Van Molle, Inge; Thomann, Andreas; Buckley, Dennis L.; So, Ernest C.; Lang, Steffen; Crews, Craig M.; Ciulli, Alessio (October 2012). "Dissecting Fragment-Based Lead Discovery at the von Hippel-Lindau Protein:Hypoxia Inducible Factor 1α Protein-Protein Interface". Chemistry & Biology. 19 (10): 1300–1312. doi:10.1016/j.chembiol.2012.08.015. PMC   3551621 . PMID   23102223.
  8. ↑ Galdeano, Carles; Gadd, Morgan S.; Soares, Pedro; Scaffidi, Salvatore; Van Molle, Inge; Birced, Ipek; Hewitt, Sarah; Dias, David M.; Ciulli, Alessio (23 October 2014). "Structure-Guided Design and Optimization of Small Molecules Targeting the Protein–Protein Interaction between the von Hippel–Lindau (VHL) E3 Ubiquitin Ligase and the Hypoxia Inducible Factor (HIF) Alpha Subunit with in Vitro Nanomolar Affinities". Journal of Medicinal Chemistry. 57 (20): 8657–8663. doi:10.1021/jm5011258. PMC   4207132 . PMID   25166285.
  9. ↑ Maniaci, Chiara; Hughes, Scott J.; Testa, Andrea; Chen, Wenzhang; Lamont, Douglas J.; Rocha, Sonia; Alessi, Dario R.; Romeo, Roberto; Ciulli, Alessio (10 October 2017). "Homo-PROTACs: bivalent small-molecule dimerizers of the VHL E3 ubiquitin ligase to induce self-degradation". Nature Communications. 8 (1): 830. Bibcode:2017NatCo...8..830M. doi:10.1038/s41467-017-00954-1. PMC   5635026 . PMID   29018234.
  10. ↑ Cardote, Teresa A. F.; Ciulli, Alessio (21 September 2017). "Structure-Guided Design of Peptides as Tools to Probe the Protein–Protein Interaction between Cullin-2 and Elongin BC Substrate Adaptor in Cullin RING E3 Ubiquitin Ligases". ChemMedChem. 12 (18): 1491–1496. doi:10.1002/cmdc.201700359. PMC   5639367 . PMID   28776949.
  11. ↑ "David Phillips fellows".
  12. ↑ "Alessio Ciulli awarded an ERC Starting Grant | Yusuf Hamied Department of Chemistry".
  13. ↑ "The EFMC Prizes for Young Medicinal Chemists".
  14. ↑ "ICBS Young Chemical Biologist Awards". International Chemical Biology Society.
  15. ↑ "Capps Green Zomaya Award". RSC Biological and Medicinal Chemistry Sector.
  16. ↑ "Dr Alessio Ciulli wins 2016 Emerging Investigator Lectureship – RSC Medicinal Chemistry Blog".
  17. ↑ "Drug Discovery Award for Alessio Ciulli". University of Dundee.
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