(1) Background: Disfunctions in autophagy machinery have been identified in various conditions, including neurodegenerative diseases, cancer, and inflammation. Among mammalian autophagy proteins, the Atg8 family member GABARAP has been shown to be greatly involved in the autophagy process of prostate cancer cells, supporting the idea that GABARAP inhibitors could be valuable tools to fight the progression of tumors. (2) Methods: In this paper, starting from the X-ray crystal structure of GABARAP in a complex with an AnkirinB-LIR domain, we identify two new peptides by applying in silico drug design techniques. The two ligands are synthesized, biophysically assayed, and biologically evaluated to ascertain their potential anticancer profile. (3) Results: Two cyclic peptides (WC8 and WC10) displayed promising biological activity, high conformational stability (due to the presence of disulfide bridges), and Kd values in the low micromolar range. The anticancer assays, performed on PC-3 cells, proved that both peptides exhibit antiproliferative effects comparable to those of peptide K1, a known GABARAP inhibitor. (4) Conclusions: WC8 and WC10 can be considered new GABARAP inhibitors to be employed as pharmacological tools or even templates for the rational design of new small molecules.

Focused Design of Novel Cyclic Peptides Endowed with GABARAP-Inhibiting Activity / E.M.A. Fassi, M. Garofalo, J. Sgrignani, M.V. Dei Cas, M. Mori, G. Roda, A. Cavalli, G. Grazioso. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1422-0067. - 23:9(2022 May 03), pp. 5070.1-5070.13. [10.3390/ijms23095070]

Focused Design of Novel Cyclic Peptides Endowed with GABARAP-Inhibiting Activity

Enrico Mario Alessandro Fassi;Michele Dei Cas;Matteo Mori;Gabriella Roda;Giovanni Grazioso
2022-05-03

Abstract

(1) Background: Disfunctions in autophagy machinery have been identified in various conditions, including neurodegenerative diseases, cancer, and inflammation. Among mammalian autophagy proteins, the Atg8 family member GABARAP has been shown to be greatly involved in the autophagy process of prostate cancer cells, supporting the idea that GABARAP inhibitors could be valuable tools to fight the progression of tumors. (2) Methods: In this paper, starting from the X-ray crystal structure of GABARAP in a complex with an AnkirinB-LIR domain, we identify two new peptides by applying in silico drug design techniques. The two ligands are synthesized, biophysically assayed, and biologically evaluated to ascertain their potential anticancer profile. (3) Results: Two cyclic peptides (WC8 and WC10) displayed promising biological activity, high conformational stability (due to the presence of disulfide bridges), and Kd values in the low micromolar range. The anticancer assays, performed on PC-3 cells, proved that both peptides exhibit antiproliferative effects comparable to those of peptide K1, a known GABARAP inhibitor. (4) Conclusions: WC8 and WC10 can be considered new GABARAP inhibitors to be employed as pharmacological tools or even templates for the rational design of new small molecules.
peptide; GABARAP inhibitors; autophagy; cancer; Atg8; LIR motif; PC-3
Settore CHIM/08 - Chimica Farmaceutica
Settore MED/43 - Medicina Legale
PSR2015-1715MCARI_M - PIANO DI SOSTEGNO ALLA RICERCA 2015-2017 - LINEA 2 "DOTAZIONE ANNUALE PER ATTIVITA' ISTITUZIONALE" - CARINI, MARINA - PSR2015-17 - Piano di sviluppo di ricerca 2015-17 - 2015
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/925882
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