Structure-based drug design articles within Nature Communications

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• Article
  25 April 2024 | Open Access

  Group 3 medulloblastoma transcriptional networks collapse under domain specific EP300/CBP inhibition

  The differential effects of targeting individual domains of multidomain enzymatic proteins are generally poorly understood. Here, the authors demonstrate lineage-specific sensitivities to domain-specific inhibition of EP300/CBP proteins across cancer and link these effects in group 3 medulloblastoma to control of a transcriptional dependency network.

  • Noha A. M. Shendy
  • , Melissa Bikowitz
  •  & Adam D. Durbin

• Article
  22 April 2024 | Open Access

  Prospective de novo drug design with deep interactome learning

  The use of data-driven generative models for drug design is challenging due to the scarcity of data. Here, the authors introduce a “zero-shot" generative deep model to enable the generation of molecules by both structure- and ligand-based drug design and apply it to design PPARγ agonists with desired properties.

  • Kenneth Atz
  • , Leandro Cotos
  •  & Gisbert Schneider

• Article
  05 March 2024 | Open Access

  Homo-BacPROTAC-induced degradation of ClpC1 as a strategy against drug-resistant mycobacteria

  Antimicrobial resistance is a global health threat and the development of alternative strategies to overcome it is of high interest. Here, the authors report proteolysis targeting chimeras active in bacteria (BacPROTACs) that bind to ClpC1, a component of the mycobacterial protein degradation machinery, and apply them for targeting a range of mycobacterial strains, including antibiotic-resistant ones.

  • Lukas Junk
  • , Volker M. Schmiedel
  •  & Guido Boehmelt

• Article
  17 February 2024 | Open Access

  Cyclic peptides discriminate BCL-2 and its clinical mutants from BCL-X_L by engaging a single-residue discrepancy

  Pro-survival B-cell lymphoma-2 (BCL-2) family proteins BCL-2 and BCL-X_L are the targets of anti-tumour drugs, but resistance is emerging. The authors present cyclic peptides against BCL-2 and BCL-X_L, with a distinct mechanism of targeting characterised.

  • Fengwei Li
  • , Junjie Liu
  •  & Dalei Wu

• Article
  06 February 2024 | Open Access

  SQM2.20: Semiempirical quantum-mechanical scoring function yields DFT-quality protein–ligand binding affinity predictions in minutes

  The paper presents the universal QM-based scoring function that accurately and rapidly predicts protein-ligand binding affinities, outperforming current computational tools. This is demonstrated on the PL-REX experimental benchmark dataset.

  • Adam Pecina
  • , Jindřich Fanfrlík
  •  & Jan Řezáč

• Article
  02 January 2024 | Open Access

  Avapritinib-based SAR studies unveil a binding pocket in KIT and PDGFRA

  Avapritinib, a potent inhibitor, offers hope for D842V-mutant GIST patients with high response rates; however, resistance and side effects remain challenges. Here, crystal structures shed light on this and reveal a Gα-pocket for drug development.

  • A. Teuber
  • , T. Schulz
  •  & D. Rauh

• Article
  10 October 2023 | Open Access

  Structure-based design of a phosphotyrosine-masked covalent ligand targeting the E3 ligase SOCS2

  SH2 domains are challenging to target using small molecules. Here, the authors develop phosphotyrosine-based covalent ligands of the E3 ligase SOCS2 using structure-based design. A pro-drug approach yields cell active inhibitors that block SOCS2 substrate recruitment.

  • Sarath Ramachandran
  • , Nikolai Makukhin
  •  & Alessio Ciulli

• Article
  07 September 2023 | Open Access

  Discovery of a selective and biologically active low-molecular weight antagonist of human interleukin-1β

  Interleukin-1β is a pro-inflammatory cytokine of medical importance. Here the authors describe the discovery of a low-molecular weight compound that antagonizes hIL-1β function in cells, demonstrating the relevance of this discovery for future development of hIL-1β directed therapeutics.

  • Ulrich Hommel
  • , Konstanze Hurth
  •  & Frédéric Bornancin

• Article
  24 August 2023 | Open Access

  Structural basis of lipid-droplet localization of 17-beta-hydroxysteroid dehydrogenase 13

  Hydroxysteroid 17-beta-dehydrogenase 13 (HSD17B13) is a hepatic lipid droplet-associated enzyme that is upregulated in patients with non-alcoholic fatty liver disease. Here, the authors report crystal structures of HSD17B13 and its complexes with two series of inhibitors.

  • Shenping Liu
  • , Ruth F. Sommese
  •  & Michelle F. Clasquin

• Article
  22 June 2023 | Open Access

  Non-covalent inhibitors of thioredoxin glutathione reductase with schistosomicidal activity in vivo

  Only praziquantel is available for treating schistosomiasis, a disease affecting >200 million people. Here, the authors identify compounds active against schistosome infections meeting the criteria for lead progression indicated by WHO with better activity against juvenile worms than praziquantel.

  • Valentina Z. Petukhova
  • , Sammy Y. Aboagye
  •  & Pavel A. Petukhov

• Article
  29 May 2023 | Open Access

  From a drug repositioning to a structure-based drug design approach to tackle acute lymphoblastic leukemia

  Deoxycytidine kinase is the rate-limiting enzyme of the salvage pathway and it has recently emerged as a target for antiproliferative therapies for cancers where it is essential. Here, the authors develop a potent inhibitor applying an iterative multidisciplinary approach, which relies on computational design coupled with experimental evaluations.

  • Magali Saez-Ayala
  • , Laurent Hoffer
  •  & Xavier Morelli

• Article
  02 March 2023 | Open Access

  A covalent BTK ternary complex compatible with targeted protein degradation

  Bridging covalent ligand discovery with chimeric degrader design has emerged as a mechanism to target proteins that lack enzymatic activity or are intractable. Here, the authors use biochemical and cellular tools to deconvolute the role of covalent modification in targeted protein degradation using Bruton’s tyrosine kinase.

  • James Schiemer
  • , Andrew Maxwell
  •  & Matthew F. Calabrese

• Article
  20 December 2022 | Open Access

  Synthesis of macrocyclic nucleoside antibacterials and their interactions with MraY

  MraY is a membrane enzyme required for bacterial cell wall synthesis. Here, the authors modify sphaerimicins as antibacterials targeting it via structure-based design and synthesis through two key reactions, showing a platform for further development of MraY inhibitors as antibacterials.

  • Takeshi Nakaya
  • , Miyuki Yabe
  •  & Satoshi Ichikawa

• Article
  02 December 2022 | Open Access

  Chemoenzymatic synthesis of sulfur-linked sugar polymers as heparanase inhibitors

  Heparin is a family of complex carbohydrates binding to proteins to modulate cell activities. Here the authors report the synthesis, and conformations simulations of S-linked hemi-A heparosan [GlcA-S-GlcNAc]_n, a thio-glycosidic uncleavable polysaccharide, and test it as human heparanase inhibitor.

  • Peng He
  • , Xing Zhang
  •  & Paul L. DeAngelis

• Article
  12 November 2022 | Open Access

  Generative deep learning enables the discovery of a potent and selective RIPK1 inhibitor

  Retrieval of a new starting active compound with a novel scaffold during early drug development is an important but challenging task. Here, the authors propose a generative deep learning model and by applying this model they discover a potent and highly selective RIPK1 inhibitor with a previously unreported scaffold.

  • Yueshan Li
  • , Liting Zhang
  •  & Shengyong Yang

• Article
  28 October 2022 | Open Access

  Chemical space docking enables large-scale structure-based virtual screening to discover ROCK1 kinase inhibitors

  Virtual screening of huge libraries is successful in identifying drug leads. Here, the authors describe a computational strategy, Chemical Space Docking, which combines docking with a reaction-based search of compounds, thereby enabling the exploration of billions of compounds and beyond.

  • Paul Beroza
  • , James J. Crawford
  •  & Christian Lemmen

• Article
  11 October 2022 | Open Access

  Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs

  Tuberculosis is a major cause of mortality, and the rise of drug-resistant strains of Mycobacterium tuberculosis requires the urgent development of safe and effective treatments. In this work, the authors develop a compound against lysyl-tRNA synthetase, demonstrating on-target mechanism of action and efficacy in vivo.

  • Simon R. Green
  • , Susan H. Davis
  •  & Laura A. T. Cleghorn

• Article
  10 October 2022 | Open Access

  A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo

  Protein degraders are an emerging drug modality; however, their properties lie beyond typical drug-like space. Here the authors report optimisation via structure-based exit vector and linker design towards the VHL-recruiting PROTAC ACBI2, an orally bioavailable and selective degrader of SMARCA2.

  • Christiane Kofink
  • , Nicole Trainor
  •  & William Farnaby

• Article
  20 September 2022 | Open Access

  Insight into mode-of-action and structural determinants of the compstatin family of clinical complement inhibitors

  Therapeutic modulation of the complement system has gained interest over the past two decades. Here, the authors provide molecular-level insight into the mode-of-action, target selectivity and species specificity of the compstatin family of complement inhibitors, which entered the clinic in 2021.

  • Christina Lamers
  • , Xiaoguang Xue
  •  & Daniel Ricklin

• Article
  15 September 2022 | Open Access

  Structure of the active G_i-coupled human lysophosphatidic acid receptor 1 complexed with a potent agonist

  LPA₁ is one of the GPCRs that are drug targets for various diseases. Here the authors report a cryo-EM structure of the active human LPA₁-G_i complex bound to an LPA analog with more potent activity against LPA₁ and clarified the ligand recognition mechanism.

  • Hiroaki Akasaka
  • , Tatsuki Tanaka
  •  & Osamu Nureki

• Article
  12 September 2022 | Open Access

  Identification of a binding site on soluble RANKL that can be targeted to inhibit soluble RANK-RANKL interactions and treat osteoporosis

  Huang et al. discover a binding site on soluble RANKL that is not found on its membrane-bound homologue. A drug screening identified a small molecule (S3-15) that can target this binding site and has anti-osteoporotic but not immunosuppressive effects.

  • Dane Huang
  • , Chao Zhao
  •  & Jun Xu

• Article
  24 August 2022 | Open Access

  Rational design of a sensitivity-enhanced tracer for discovering efficient APC–Asef inhibitors

  The adenomatous polyposis coli (APC)–Asef protein interaction is essential for colorectal cancer metastasis. Here, the authors present the rational design of a sensitivity-enhanced tracer for fluorescence polarization assays, enabling them to discover more efficient APC–Asef interaction inhibitors.

  • Jie Zhong
  • , Yuegui Guo
  •  & Jian Zhang

• Article
  12 July 2022 | Open Access

  An LNA-amide modification that enhances the cell uptake and activity of phosphorothioate exon-skipping oligonucleotides

  Oligonucleotides targeting mRNA are promising therapeutic agents but suffer from poor bioavailability. Here, the authors develop reduced-charge oligonucleotides with artificial LNA-amide linkages with improved cell uptake and minimal structural deviation to the DNA:RNA duplex.

  • Ysobel R. Baker
  • , Cameron Thorpe
  •  & Tom Brown

• Article
  27 April 2022 | Open Access

  Covalent narlaprevir- and boceprevir-derived hybrid inhibitors of SARS-CoV-2 main protease

  Three covalent hybrid inhibitors of SARS-CoV-2 main protease (Mpro) have been designed and compared to Pfizer’s nirmatrelvir (PF-07321332), providing atomic and thermodynamic details of their binding to the enzyme, and antiviral potency.

  • Daniel W. Kneller
  • , Hui Li
  •  & Andrey Kovalevsky

• Article
  25 April 2022 | Open Access

  An unexpected strategy to alleviate hypoxia limitation of photodynamic therapy by biotinylation of photosensitizers

  Type I photodynamic therapy (PDT) sensitizers show good hypoxia tolerance but only few strategies are available for the design of purely organic Type I photosensitizers (PS). Here, the authors use biotinylation as design strategy to obtain PS-Biotin sensitizers with high efficiency for the generation of superoxide anion radicals and singlet oxygen.

  • Jing An
  • , Shanliang Tang
  •  & Wen-Heng Zheng

• Article
  10 February 2022 | Open Access

  Small molecule SWELL1 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes

  Type 2 diabetes is associated with insulin resistance, impaired insulin secretion and liver steatosis. Here the authors report a proof-of-concept study for small molecule SWELL1 modulators as a therapeutic approach to treat diabetes and associated liver steatosis by enhancing systemic insulin-sensitivity and insulin secretion in mice.

  • Susheel K. Gunasekar
  • , Litao Xie
  •  & Rajan Sah

• Article
  08 February 2022 | Open Access

  Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate

  Liu et al. report structures of human sphingosine 1-phosphate (S1P) receptor 1 (S1P₁) in complex with Gi and S1P or the multiple sclerosis (MS) drug Siponimod, as well as human lysophosphatidic acid (LPA) receptor 1 (LPA₁) in complex with Gi and LPA, revealing distinct conformations of the lysophospholipids interacting with their cognate GPCRs.

  • Shian Liu
  • , Navid Paknejad
  •  & Xin-Yun Huang

• Article
  28 January 2022 | Open Access

  Decisive role of water and protein dynamics in residence time of p38α MAP kinase inhibitors

  The molecular determinants of the residence time of a small molecule inhibitor at its target protein are not well understood. Here, Pantsar et al. show that the target protein’s conformational stability and solvent exposure are key factors governing the target residence time of kinase inhibitors.

  • Tatu Pantsar
  • , Philipp D. Kaiser
  •  & Stefan A. Laufer

• Article
  08 December 2021 | Open Access

  Sliding of HIV-1 reverse transcriptase over DNA creates a transient P pocket – targeting P-pocket by fragment screening

  Here the authors observe a transient P-pocket created when  HIV reverse transcriptase slides over DNA substrate, identify  fragments  targeting this pocket, and develop a cryo-EM platform for lead optimization.

  • Abhimanyu K. Singh
  • , Sergio E. Martinez
  •  & Kalyan Das

• Article
  25 November 2021 | Open Access

  Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity,

  Simultaneous targeting of BCL-xL and BCL-2 is an attractive approach for cancer treatment. Based on information gained by computational structure modelling, the authors develop a PROTAC that induces degradation of both BCL-xL and BCL-2 and effectively targets BCL-xL/2-dependent leukaemia cells.

  • Dongwen Lv
  • , Pratik Pal
  •  & Daohong Zhou

• Article
  27 October 2021 | Open Access

  Structure of PDE3A–SLFN12 complex and structure-based design for a potent apoptosis inducer of tumor cells

  Anagrelide, nauclefine and DNMDP induce apoptosis by forming complexes with phosphodiesterase 3A (PDE3A) and Schlafen 12 protein (SLFN12). Here, the authors present the cryo-EM structures of PDE3A-SLFN12 complexes with these compounds as molecular glues. Based on the complex structure, they developed an anagrelide analog that shows a higher potency in inducing apoptosis in cultured cells and also promotes tumor growth inhibition in tumor xenografts, which is of interest for cancer drug development.

  • Jie Chen
  • , Nan Liu
  •  & Xiaodong Wang

• Article
  06 September 2021 | Open Access

  Cellular model system to dissect the isoform-selectivity of Akt inhibitors

  Elucidating specific effects of protein kinase Akt isoforms remains challenging. Here, the authors establish an Akt isoform-dependent cellular model system and use it, together with X-ray crystallography and structure-based ligand design, to develop isoform-selective covalent-allosteric Akt inhibitors

  • Lena Quambusch
  • , Laura Depta
  •  & Daniel Rauh

• Article
  25 June 2021 | Open Access

  Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function

  Amyloid aggregation of mutant p53 contributes to its loss of tumor suppressor function and oncogenic gain-of-function. Here, the authors use a protein mimetic to abrogate mutant p53 aggregation and rescue p53 function, which inhibits cancer cell proliferation in vitro and halts tumor growth in vivo.

  • L. Palanikumar
  • , Laura Karpauskaite
  •  & Mazin Magzoub

• Article
  14 May 2021 | Open Access

  Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity

  The histone methyltransferase ASH1L plays a role in various diseases, including cancer, and has been validated as a therapeutic target; however, no inhibitors of ASH1L have been reported. Here the authors present small molecule inhibitors of ASH1L and demonstrate their on-target activity in leukemia cells and a mouse model of leukemia.

  • David S. Rogawski
  • , Jing Deng
  •  & Jolanta Grembecka

• Article
  11 May 2021 | Open Access

  Selective inhibition of cullin 3 neddylation through covalent targeting DCN1 protects mice from acetaminophen-induced liver toxicity

  Activation of cullin-RING ligases can be inhibited by targeting DCN1, but selective DCN1 inhibitors with in vivo activity are lacking. Here, the authors develop covalent DCN1 inhibitors that selectively and potently inhibit cullin-3 activation and downstream functions in cells and in mice.

  • Haibin Zhou
  • , Jianfeng Lu
  •  & Shaomeng Wang

• Article
  25 March 2021 | Open Access

  Structure-based design of a Cortistatin analogue with immunomodulatory activity in models of inflammatory bowel disease

  Inflammatory bowel disease is caused by chronic inflammation of the gastrointestinal tract and disturbed immune responses. Here the authors present examination of Cortistatin analogues that display enhanced half-life stability whilst maintaining immunomodulatory functionality.

  • Álvaro Rol
  • , Toni Todorovski
  •  & Maria J. Macias

• Article
  16 February 2021 | Open Access

  Fast acting allosteric phosphofructokinase inhibitors block trypanosome glycolysis and cure acute African trypanosomiasis in mice

  Glycolytic enzymes are challenging drug targets due to their highly conserved active sites and phosphorylated substrates. Here, the authors identify fast acting allosteric inhibitors of Trypanosoma brucei phosphofructokinase that block trypanosome glycolysis and provide cure evidence in murine model.

  • Iain W. McNae
  • , James Kinkead
  •  & Malcolm D. Walkinshaw

• Article
  25 November 2020 | Open Access

  Designed CXCR4 mimic acts as a soluble chemokine receptor that blocks atherogenic inflammation by agonist-specific targeting

  The development of specific anti-cytokine/chemokine therapeutic strategies for atherosclerotic disease is challenging. Here, the authors have designed a peptide-based ectodomain mimic of the chemokine receptor CXCR4 that selectively targets MIF but not CXCL12 and blocks experimental atherosclerosis in vivo.

  • Christos Kontos
  • , Omar El Bounkari
  •  & Jürgen Bernhagen

• Article
  16 November 2020 | Open Access

  AdipoR1/AdipoR2 dual agonist recovers nonalcoholic steatohepatitis and related fibrosis via endoplasmic reticulum-mitochondria axis

  Nonalcoholic steatohepatitis (NASH) and associated liver fibrosis have limited therapy options. Here the authors report a novel adiponectin-based dual agonist for adiponectin receptors 1 and 2 with a longer half-life, and show that it ameliorates NASH and liver fibrosis in mouse models.

  • Hongjiao Xu
  • , Qian Zhao
  •  & Xianxing Jiang

• Article
  07 August 2020 | Open Access

  Structure-based evolution of a promiscuous inhibitor to a selective stabilizer of protein–protein interactions

  Small molecule stabilizers of protein–protein interactions hold great therapeutic potential. Based on virtual screening and molecular docking, the authors here develop a strategy to evolve weak, promiscuous inhibitors of 14-3-3 interactions into selective stabilizers of the 14-3-3/ChREBP complex.

  • Eline Sijbesma
  • , Emira Visser
  •  & Christian Ottmann

• Article
  19 December 2019 | Open Access

  Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer

  While biologics have been successfully applied in TNF antagonist treatments, there are no clinically approved small molecules that target TNF. Here, the authors discover potent small molecule inhibitors of TNF, elucidate their molecular mechanism, and demonstrate TNF inhibition in vitro and in vivo.

  • James O’Connell
  • , John Porter
  •  & Alastair Lawson

• Article
  19 September 2019 | Open Access

  Harnessing calcineurin-FK506-FKBP12 crystal structures from invasive fungal pathogens to develop antifungal agents

  FK506 is a potential antifungal compound that inhibits calcineurin, but it also has immunosuppressive activity. Here, Juvvadi et al. report the structure of FK506 in complex with the FK506-binding protein FKPB12 and calcineurin, and design a less immunosuppresive FK506 analog with antifungal activity in mice.

  • Praveen R. Juvvadi
  • , David Fox III
  •  & William J. Steinbach

• Article
  09 January 2019 | Open Access

  Structure and inhibition mechanism of the catalytic domain of human squalene epoxidase

  Squalene epoxidase (SQLE) is a key enzyme in cholesterol biosynthesis and is a target for hypercholesteremia and cancer drug development. Here the authors present the crystal structures of the human SQLE catalytic domain alone and bound with small molecule inhibitors, which will facilitate the development of next-generation SQLE inhibitors.

  • Anil K. Padyana
  • , Stefan Gross
  •  & Gromoslaw A. Smolen

• Article
  03 January 2019 | Open Access

  Lattice engineering enables definition of molecular features allowing for potent small-molecule inhibition of HIV-1 entry

  Temsavir, a compound that inhibits HIV entry by binding envelope (Env), is currently in clinical development. Here, Lai et al. identify a more than 10-fold improved compound and, using lattice engineering, obtain crystal structures that give insights into improved inhibition between small molecules and Env.

  • Yen-Ting Lai
  • , Tao Wang
  •  & Peter D. Kwong

• Article
  17 December 2018 | Open Access

  Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia

  High expression of Mcl-1 promotes tumorigenesis and resistance to anticancer therapies. Here they report a macrocyclic molecule with high selectivity and affinity for Mcl-1 that exhibits potent anti-tumor effects as single agent and in combination with bortezomib or venetoclax in preclinical models of multiple myeloma and acute myeloid leukemia.

  • Adriana E. Tron
  • , Matthew A. Belmonte
  •  & Alexander W. Hird

• Article
  09 November 2018 | Open Access

  Design and 22-step synthesis of highly potent D-ring modified and linker-equipped analogs of spongistatin 1

  Step-economical and efficient syntheses of Spongistatin 1 analogs are desirable for the development of potent anti-proliferative agents. Here, the authors report a 22-step synthesis of a D-ring modified Spongistatin 1 analog with retained picomolar potency among a group of C(15) ester derivatives.

  • Linda M. Suen
  • , Makeda A. Tekle-Smith
  •  & James L. Leighton

• Article
  27 September 2018 | Open Access

  High-resolution NMR studies of antibiotics in cellular membranes

  Antibiotics that target the peptidoglycan precursor lipid II are promising templates for next-generation antibiotics. Here authors use solid-state NMR and monitor lipid II-binding antibiotics, such as nisin, directly in cell membranes.

  • João Medeiros-Silva
  • , Shehrazade Jekhmane
  •  & Markus Weingarth

• Article
  09 August 2018 | Open Access

  Small molecule inhibitors of RAS-effector protein interactions derived using an intracellular antibody fragment

  Intracellular antibodies can inhibit disease-relevant protein interactions, but inefficient cellular uptake limits their utility. Using a RAS-targeting intracellular antibody as a screening tool, the authors here identify small molecules that inhibit RAS-effector interactions and readily penetrate cells.

  • Camilo E. Quevedo
  • , Abimael Cruz-Migoni
  •  & Terence H. Rabbitts

• Article
  30 January 2018 | Open Access

  Structure-guided design of an Hsp90β N-terminal isoform-selective inhibitor

  The molecular chaperone Hsp90 oversees the folding of many proteins associated with cancer progression but existing small-molecule inhibitors of this pathway are not isoform-selective. Here, the authors rationally design an Hsp90 inhibitor that displays high selectivity for the Hsp90β isoform.

  • Anuj Khandelwal
  • , Caitlin N. Kent
  •  & Brian S. J. Blagg

• Article
  09 June 2017 | Open Access

  A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action

  PIN1 is a promising therapeutic target for cancer treatment. In this study, the authors identify a covalent inhibitor of PIN1 with anti-tumour and anti-metastatic properties thanks to PIN1 inactivation and to the release, after binding to PIN1, of a quinone-mimicking compound that elicits reactive oxygen generation and causes DNA damage.

  • Elena Campaner
  • , Alessandra Rustighi
  •  & Giannino Del Sal