Humanizing plant-derived snakins and their encrypted antimicrobial peptides

Due to safety restrictions, plant-derived antimicrobial peptides (AMPs) need optimization to be consumed beyond preservatives. Herein, 175 GASA-domain-containing snakins were analyzed. Factors including charge, hydrophobicity, helicity, hydrophobic moment (μH), folding enthalpy, folding heat capacity, folding free energy, therapeutic index, allergenicity, and bitterness were considered. The most optimal snakins for oral consumption as preservatives were from Cajanus cajan, Cucumis melo, Durio zibethinus, Glycine soja, Herrania umbratica, and Ziziphus jujuba. Virtual digestion of snakins predicted ACE1 and DPPIV inhibitory as dominant effects upon oral use with antihypertensive and antidiabetic properties. To be applied as a therapeutic in parenteral administration, snakins were browsed for short 20-mer encrypted fragments that were non-toxic or with eliminated toxicity using directed mutagenesis yet retaining the AMP property. The most promising 20-mer AMPs were Mr-SNK2-1a in Morella rubra with BBB permeation, Na-SNK2-2a(C18W), and Na-SNK2-2b(C16F) from Nicotiana attenuata. These AMPs were cell-penetrating peptides (CPPs), with a charge of +6, a μH of about 0.40, and a Boman-index higher than 2.48 Kcalmol-1. Na-SNK2-2a(C18W) had putative activity against gram-negative bacteria with MIC lower than 25 μgml-1, and Na-SNK2-2b(C16F) was a potential anti-HIV with an IC50 of 3.04 μM. Other 20-mer AMPs, such as Cc-SNK1-2a from Cajanus cajan displayed an anti-HCV property with an IC50 of 13.91 μM. While Si-SNK2-3a(C17P) from Sesamum indicum was a cationic anti-angiogenic CPP targeting the acidic microenvironment of tumors, Cme-SNK2-1a(C11F) from Cucumis melo was an immunomodulator CPP applicable as a vaccine adjuvant. Because of combined mechanisms, investigating cysteine-rich peptides can nominate effective biotherapeutics.