Contact person: Menotti Ruvo, menotti.ruvo
unina.itActors: Nunzianna Doti, nunzia.doti
gmail.com, Annamaria Sandomenico, annamaria.sandomenicogmail.com, Menotti Ruvo, menotti.ruvounina.it, Combinatorially generated molecular repertoires arelargely used to identify novel bioactive compounds. Ever more sophisticatedtechnological solutions are continuously proposed to simplify and speed up suchprocess, expanding the chemical diversity space and increasing the prospect toselect new molecular entities with specific and potent activities againsttargets of therapeutic relevance. In this context, we have used random mixturesof oligomeric peptides that represent a continuous source of bioactivemolecules with potencies ranging from the sub-nM to µM concentration. They areemployed as “synthetic broths” of structurally and chemically diversifiedmolecular fragments from which lead compounds can be extracted and further developed.We have reported many applications of combinatorial mixtures of syntheticpeptides with different complexity and engrafted on diverse structuralscaffolds. We have used such methodologies for preparing and screeninglibraries of small peptides to identify protein binders and inhibitors of protein-proteininteractions, some of which have reached invivo testing in animals [1-8] and testingon patients [9-12] . Among the others we have developedsmall bioactive peptides binding VEGFR1 and VEGFR2 [ 1-5,7] , Cripto-1 [2, 5, 6] , ALK4 [8] and the complex GADD45 β /MKK7 [ 9-12] for therapeuticand diagnostic applications in cancer. The most advanced technologies inbiotechnology, engineering and computer science are also currently applied tofacilitate the discovery of new bioactive peptides that, by binding inspecific protein cavities of therapeutic targets, acquire a therapeuticrelevance by modulating their biological activity.
We apply the solutionsprovided by all the technological advances in biotechnology, engineering andcomputer science to facilitate the discovery of new bioactive peptides that
Current efforts are devoted to the development ofinhibitors of GADD45β [2] for further applications incancer, of the AIF/Cyclophylin complex [13-18] forapplication in neurological and cardiac diseases and of the fusion between SARS-CoV2 and epithelial cells to identify newpotential antiviral drugs.
[1]Tarallo V, Iaccarino E, Cicatiello V, Sanna R, Ruvo M, De Falco S. OralDelivery of a Tetrameric Tripeptide Inhibitor of VEGFR1 Suppresses PathologicalChoroid Neovascularization. Int J Mol Sci. 2020 Jan 9;21(2):410.
[2]Sandomenico A, Caporale A, Doti N, Cross S, Cruciani G, Chambery A, De Falco S,Ruvo M. Synthetic Peptide Libraries: From Random Mixtures to In Vivo Testing.Curr Med Chem. 2020;27(6):997-1016.
[3]Calvanese L, Caporale A, Focà G, Iaccarino E, Sandomenico A, Doti N, ApicellaI, Incisivo GM, De Falco S, Falcigno L, D'Auria G, Ruvo M. Targeting VEGFreceptors with non-neutralizing cyclopeptides for imaging applications. AminoAcids. 2018 Feb;50(2):321-329.
[4]Cicatiello V, Apicella I, Tudisco L, Tarallo V, Formisano L, Sandomenico A, KimY, Bastos-Carvalho A, Orlandi A, Ambati J, Ruvo M, Bianco R, De Falco S.Powerful anti-tumor and anti-angiogenic activity of a new anti-vascularendothelial growth factor receptor 1 peptide in colorectal cancer models.Oncotarget. 2015 Apr 30;6(12):10563-76.
[5]Ruvo M, Sandomenico A, Tudisco L, De Falco S. Branched peptides for themodulation of protein-protein interactions: more arms are better than one? CurrMed Chem. 2011;18(16):2429-37.
[6]Lonardo E, Parish CL, Ponticelli S, Marasco D, Ribeiro D, Ruvo M, De Falco S,Arenas E, Minchiotti G. A small synthetic cripto blocking Peptide improvesneural induction, dopaminergic differentiation, and functional integration ofmouse embryonic stem cells in a rat model of Parkinson's disease. Stem Cells.2010 Aug;28(8):1326-37.
[7]Ponticelli S, Marasco D, Tarallo V, Albuquerque RJ, Mitola S, Takeda A, StassenJM, Presta M, Ambati J, Ruvo M, De Falco S. Modulation of angiogenesis by atetrameric tripeptide that antagonizes vascular endothelial growth factorreceptor 1. J Biol Chem. 2008 Dec 5;283(49):34250-9.
[8] Iaccarino E, Calvanese L,Untiveros G, Falcigno L, D'Auria G, Latino D, Sivaccumar JP, Strizzi L, Ruvo M,Sandomenico A. Structure-based design of small bicyclic peptide inhibitors ofCripto-1 activity. Biochem J. 2020 Apr 30;477(8):1391-1407.
[9] Tornatore L, Capece D, D'AndreaD, Begalli F, Verzella D, Bennett J, Acton G, Campbell EA, Kelly J, Tarbit M,Adams N, Bannoo S, Leonardi A, Sandomenico A, Raimondo D, Ruvo M, Chambery A,Oblak M, Al-Obaidi MJ, Kaczmarski RS, Gabriel I, Oakervee HE, Kaiser MF,Wechalekar A, Benjamin R, Apperley JF, Auner HW, Franzoso G. Preclinicaltoxicology and safety pharmacology of the first-in-class GADD45 β /MKK7 inhibitor and clinicalcandidate, DTP3. Toxicol Rep. 2019 Apr 19;6:369-379.
[10] Tornatore L, Capece D, D'AndreaD, Begalli F, Verzella D, Bennett J, Acton G, Campbell EA, Kelly J, Tarbit M,Adams N, Bannoo S, Leonardi A, Sandomenico A, Raimondo D, Ruvo M, Chambery A,Oblak M, Al-Obaidi MJ, Kaczmarski RS, Gabriel I, Oakervee HE, Kaiser MF,Wechalekar A, Benjamin R, Apperley JF, Auner HW, Franzoso G. Clinical proof ofconcept for a safe and effective NF- κ B-targeting strategy in multiple myeloma. Br J Haematol. 2019May;185(3):588-592.
[11] Rega C, Russo R, Focà A,Sandomenico A, Iaccarino E, Raimondo D, Milanetti E, Tornatore L, Franzoso G,Pedone PV, Ruvo M, Chambery A. Probing the interaction interface of the GADD45 β /MKK7 and MKK7/DTP3 complexes bychemical cross-linking mass spectrometry. Int J Biol Macromol. 2018 Jul 15;114:114-123.
[12] Tornatore L, Sandomenico A,Raimondo D, Low C, Rocci A, Tralau-Stewart C, Capece D, D'Andrea D, Bua M,Boyle E, van Duin M, Zoppoli P, Jaxa-Chamiec A, Thotakura AK, Dyson J, WalkerBA, Leonardi A, Chambery A, Driessen C, Sonneveld P, Morgan G, Palumbo A,Tramontano A, Rahemtulla A, Ruvo M, Franzoso G. Cancer-selective targeting ofthe NF- κ B survivalpathway with GADD45 β /MKK7inhibitors. Cancer Cell. 2014 Oct 13;26(4):495-508.
[13] Monti A, Sturlese M, CaporaleA, Roger JA, Mascanzoni F, Ruvo M, Doti N. Design, synthesis, structuralanalysis and biochemical studies of stapled AIF(370-394) analogues as ligand ofCypA. Biochim Biophys Acta Gen Subj. 2020 Dec;1864(12):129717.
[14] Farina B, Sturlese M,Mascanzoni F, Caporale A, Monti A, Di Sorbo G, Fattorusso R, Ruvo M, Doti N.Binding mode of AIF(370-394) peptide to CypA: insights from NMR, label-free andmolecular docking studies. Biochem J. 2018 Jul 31;475(14):2377-2393.
[15] Farina B, Di Sorbo G, ChamberyA, Caporale A, Leoni G, Russo R, Mascanzoni F, Raimondo D, Fattorusso R, RuvoM, Doti N. Structural and biochemical insights of CypA and AIF interaction. SciRep. 2017 Apr 25;7(1):1138.
[16] Hangen E, Féraud O, Lachkar S,Mou H, Doti N, Fimia GM, Lam NV, Zhu C, Godin I, Muller K, Chatzi A, Nuebel E,Ciccosanti F, Flamant S, Bénit P, Perfettini JL, Sauvat A, Bennaceur-GriscelliA, Ser-Le Roux K, Gonin P, Tokatlidis K, Rustin P, Piacentini M, Ruvo M,Blomgren K, Kroemer G, Modjtahedi N. Interaction between AIF and CHCHD4Regulates Respiratory Chain Biogenesis. Mol Cell. 2015 Jun 18;58(6):1001-14.
[17] Doti N, Reuther C, ScognamiglioPL, Dolga AM, Plesnila N, Ruvo M, Culmsee C. Inhibition of the AIF/CypA complexprotects against intrinsic death pathways induced by oxidative stress. CellDeath Dis. 2014 Jan 16;5(1):e993.
[18] Stephen P. Chelko, GizemKeceli, Andrea Carpi, Nunzianna Doti, Jacopo Agrimi, Angeliki Asimaki, CarlosBueno Beti, Matthew Miyamoto, Nuria Amat-Codina, Djahida Bedja, An-Chi Wei,Brittney Murray, Crystal Tichnell, Chulan Kwon, Hugh Calkins, Cynthia A. James,Brian O’Rourke, Marc K. Halushka, Edon Melloni, Jeffrey E. Saffitz, Daniel P.Judge, Menotti Ruvo, Richard N Kitsis, Peter Andersen, Fabio Di Lisa, andNazareno Paolocci,
Exercise triggers CAPN1-mediated AIFtruncation inducing myocyte necroptosis in
arrhythmogenic cardiomyopathy. ScienceTranslational Medicine, 2021. In press.
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