A cell-permeable Atg6/Beclin1-derived autophagy-inducing peptide (Minimum effective conc. ≤10 μM for 3 h) that effectively activates cellular Beclin1 by competing against Beclin1 for binding to its negative regulator GAPR-1/GLIPR2 on the Golgi surface. Shown to induce autosis, autophagy-dependent death, in cells of human, rat, and murine origin in a dose- and time-dependent manner (Minimum effective conc. >5 μM for 5 h in HeLa cultures), blockable by autophagy inhibitor 3-MA (10 mM, Cat. no.189490; [T-B] = 20 μM) or via Na
+/K
+-ATPase inhibition, but insensitive to Z-VAD-FMK (Cat. no.
219007) or Nec-1 (Cat. nos.
480065 &
505224) treatment. Non-cytotoxic autophagy induction with lower doses of Tat-Beclin1 and shorter exposure times is therapeutically beneficial in blocking RNA viral replications both in cultures (4 h 10 μM peptide treatment 4 h post viral infection in HeLa cultures; 0.5-5 μM peptide pre-treatment 24 h before HIV infection in human MDM cultures)
in vitro and in CHIKV-infected neonatal mice (15 mg/kg/day i.p.)
in vivo. While Tat-Beclin1 bioavailability is limited to the peripheral tissues in mice, a peptide based on Tat-Beclin1 retro-inverso sequence (Cat. no. 506416) shows efficacy in a murine model of neonatal WNV CNS infection. Note: increased drug potency is reported in acidified (pH 7.0) serum-free cultures.
