Contact person: Nunzianna Doti, nunzia.doti
gmail.comActors: Menotti Ruvo, menotti.ruvo
unina.it, Annamaria Sandomenico, annamaria.sandomenicogmail.com, Nunzianna Doti, nunzia.dotigmail.com, Protein–protein interactions (PPIs) playpivotal roles in many physiological processes. Aberrant PPIs are instead associatedwith several diseases, including cancer, infectious and neurodegenerativediseases and their disruption by selective and potent inhibitors is nowaccepted as a validated strategy for effective therapeutic treatments. TargetingPPIs through small molecule inhibitors is however a challenging task due to thelarge molecular surface involved inprotein-protein recognition and to the lack of obvious small molecule binding pockets at most protein-protein interfaces. Synthetic peptides andpeptidomimetics, instead, thanks to their generally broad conformationalflexibility and capability to adapt to binding surfaces, are gaining anincreasing interest as modulators of protein–protein interactions and many arebeing developed as new therapeutics. The main objective of the activities inthis area is the development of peptides and/or peptidomimetics that, by mimickingthe interacting protein’s binding domains, suppress PPIs involved in humandiseases. We are currently applying a multidisciplinary approach that combinesclassical molecular biology tools, High Throughput Screening (HTS), NMRanalysis, molecular modelling, binding studies, synthetic combinatorialstrategies and in vivo testing to anumber of protein complexes that underpin relevant diseases. Following thisapproach, to date, we have successfully identified selective inhibitors of thecomplexes AIF/CypA (1-6), CHCHD4/AIF (7), PREP-MEIS/PBX (8,9), PREP/p160 (10), GADD45b/MKK7(11-13) and other protein complexes involved in human diseases includingneurodegeneration, arhythmogeniccardiomyopathy and cancer. Someinhibitors are being further developed and modified to obtain sufficiently safeand effective compounds for investigations closer to the clinical use.
1. Doti N,Reuther C, Scognamiglio PL, Dolga AM, Plesnila N, Ruvo M, Culmsee C. Inhibition of the AIF/CypA complexprotects against intrinsic death pathways induced by oxidative stress. Cell DeathDis. 2014 Jan16;5(1):e993.
2. Structural and biochemical insights of CypA and AIFinteraction. Farina B, Di Sorbo G, Chambery A,Caporale A, Leoni G, Russo R, Mascanzoni F, Raimondo D, Fattorusso R, RuvoM, Doti N. Sci Rep. 2017 Apr 25;7(1):1138.
3. FarinaB, 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: insightsfrom NMR, label-free and molecular docking studies. Biochem J. 2018 Jul31;475(14):2377-2393.
4. Monti A, Sturlese M, Caporale A, Roger JA, MascanzoniF, Ruvo M, Doti N. Design, synthesis, structural analysis and biochemicalstudies of stapled AIF(370-394) analogues as ligand of CypA. Biochim Biophys Acta Gen Subj.2020 Dec;1864(12):129717.
5. Rodriguez J, Xie C, Li T, Sun Y, Wang Y, Xu Y, Li K,Zhang S, Zhou K, Wang Y, Mallard C, Hagberg H, Doti N, Wang X, Zhu C. Inhibitingthe interaction between apoptosis-inducing factor and cyclophilin A preventsbrain injury in neonatal mice after hypoxia-ischemia. Neuropharmacology. 2020Jul;171:108088.
6. ChelkoSP, Keceli G, Carpi A, Doti N, et al. Exercise triggersCAPN1-mediated AIF truncation inducing myocyte necroptosis in arrhythmogeniccardiomyopathy. Acceptedin Science Translational Medicine, 2020.
7. Hangen E,Féraud O, Lachkar S, Mou H, Doti N, et al. Interaction between AIF and CHCHD4 RegulatesRespiratory Chain Biogenesis. Mol Cell.2015 Jun 18;58(6):1001-14. doi: 10.1016/j.molcel.2015.04.020.
8. Bruckmann C, Tamburri S, De Lorenzi V, Doti N,Monti A, Mathiasen L, Cattaneo A, Ruvo M, Bachi A, Blasi F. Mappingthe native interaction surfaces of PREP1 with PBX1 by cross-linkingmass-spectrometry and mutagenesis. Sci Rep. 2020 Oct 8;10(1):16809.
9. Patent: MEIS1/PBX1inhibitors for the treatment of cancer. Filed on 16/3/2020, application n°102020000005599.
10. CimminoI, Lorenzo V, Fiory F, Doti N, Ricci S, Cabaro S, Liotti A, Vitagliano L,Longo M, Miele C, Formisano P, Beguinot F, Ruvo M, Oriente F. A peptideantagonist of Prep1-p160 interaction improves ceramide-induced insulin resistancein skeletal muscle cells. Oncotarget. 2017 May 30;8(42):71845-71858.
11. Tornatore L, Sandomenico A, Raimondo D, Low C, RocciA, Tralau-Stewart C, Capece D, D'Andrea D, Bua M, Boyle E, van Duin M, ZoppoliP, Jaxa-Chamiec A, Thotakura AK, Dyson J, Walker BA, Leonardi A, Chambery A,Driessen C, Sonneveld P, Morgan G, Palumbo A, Tramontano A, Rahemtulla A, RuvoM, Franzoso G. Cancer-selective targeting of the NF-κB survival pathway withGADD45β/MKK7 inhibitors. Cancer Cell. 2014 Oct 13;26(4):495-508.
12. Rega C, Russo R, Focà A, Sandomenico A, Iaccarino E,Raimondo D, Milanetti E, Tornatore L, Franzoso G, Pedone PV, Ruvo M, ChamberyA. Probing the interaction interface of the GADD45β/MKK7 and MKK7/DTP3complexes by chemical cross-linking mass spectrometry. Int J Biol Macromol.2018 Jul 15;114:114-123.
13. Tornatore L, Capece D, D'Andrea D, Begalli F, VerzellaD, 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. Preclinical toxicology and safetypharmacology of the first-in-class GADD45β/MKK7 inhibitor and clinicalcandidate, DTP3. Toxicol Rep. 2019 Apr 19;6:369-379.
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