TY - JOUR
T1 - Conformational Analysis of the Host-Defense Peptides Pseudhymenochirin-1Pb and -2Pa and Design of Analogues with Insulin-Releasing Activities and Reduced Toxicities
AU - Manzo, Giorgia
AU - Scorciapino, Mariano Andrea
AU - Srinivasan, Dinesh
AU - Attoub, Samir
AU - Mangoni, Maria Luisa
AU - Rinaldi, Andrea C.
AU - Casu, Mariano
AU - Flatt, Peter R.
AU - Conlon, J. Michael
N1 - Funding Information:
This work was supported by funds from the Sardinia Regional Government 525, L.R. 7/2007, bando 2009 (grant no. CRP- 17385), Sapienza University of Rome (grant no. C26A14STJZ), the SAAD Contract and Trading Company, Ulster University Strategic Research Funding, and U.A.E. National Research Foundation. The authors thank K. Arafat and S. Sulaiman, U.A.E. University, for technical assistance.
Publisher Copyright:
© 2015 The American Chemical Society and American Society of Pharmacognosy.
PY - 2015/12/24
Y1 - 2015/12/24
N2 - Pseudhymenochirin-1Pb (Ps-1Pb; IKIPSFFRNILKKVGKEAVSLIAGALKQS) and pseudhymenochirin-2Pa (Ps-2Pa; GIFPIFAKLLGKVIKVASSLISKGRTE) are amphibian peptides with broad spectrum antimicrobial activities and cytotoxicity against mammalian cells. In the membrane-mimetic solvent 50% (v/v) trifluoroethanol-H2O, both peptides adopt a well-defined α-helical conformation that extends over almost all the sequence and incorporates a flexible bend. Both peptides significantly (p < 0.05) stimulate the rate of release of insulin from BRIN-BD11 clonal β-cells at concentrations ≥ 0.1 nM but produce loss of integrity of the plasma membrane at concentrations ≥ 1 ΜM. Increasing cationicity by the substitution Glu17' l-Lys in Ps-1Pb and Glu27' l-Lys in Ps-2Pa generates analogues with increased cytotoxicity and reduced insulin-releasing potency. In contrast, the analogues [R8r]Ps-1Pb and [K8k,K19k]Ps-2Pa, incorporating d-amino acid residues to destabilize the α-helical domains, retain potent insulin-releasing activity but are nontoxic to BRIN-BD11 cells at concentrations of 3 ΜM. [R8r]Ps-1Pb produces a significant increase in insulin release rate at 0.3 nM and [K8k,K19k]Ps-2Pa at 0.01 nM. Both analogues show low hemolytic activity (IC50 > 100 ΜM) but retain broad-spectrum antimicrobial activity and remain cytotoxic to a range of human tumor cell lines, albeit with lower potency than the naturally occurring peptides. These analogues show potential for development into agents for type 2 diabetes therapy.
AB - Pseudhymenochirin-1Pb (Ps-1Pb; IKIPSFFRNILKKVGKEAVSLIAGALKQS) and pseudhymenochirin-2Pa (Ps-2Pa; GIFPIFAKLLGKVIKVASSLISKGRTE) are amphibian peptides with broad spectrum antimicrobial activities and cytotoxicity against mammalian cells. In the membrane-mimetic solvent 50% (v/v) trifluoroethanol-H2O, both peptides adopt a well-defined α-helical conformation that extends over almost all the sequence and incorporates a flexible bend. Both peptides significantly (p < 0.05) stimulate the rate of release of insulin from BRIN-BD11 clonal β-cells at concentrations ≥ 0.1 nM but produce loss of integrity of the plasma membrane at concentrations ≥ 1 ΜM. Increasing cationicity by the substitution Glu17' l-Lys in Ps-1Pb and Glu27' l-Lys in Ps-2Pa generates analogues with increased cytotoxicity and reduced insulin-releasing potency. In contrast, the analogues [R8r]Ps-1Pb and [K8k,K19k]Ps-2Pa, incorporating d-amino acid residues to destabilize the α-helical domains, retain potent insulin-releasing activity but are nontoxic to BRIN-BD11 cells at concentrations of 3 ΜM. [R8r]Ps-1Pb produces a significant increase in insulin release rate at 0.3 nM and [K8k,K19k]Ps-2Pa at 0.01 nM. Both analogues show low hemolytic activity (IC50 > 100 ΜM) but retain broad-spectrum antimicrobial activity and remain cytotoxic to a range of human tumor cell lines, albeit with lower potency than the naturally occurring peptides. These analogues show potential for development into agents for type 2 diabetes therapy.
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U2 - 10.1021/acs.jnatprod.5b00843
DO - 10.1021/acs.jnatprod.5b00843
M3 - Article
C2 - 26606380
AN - SCOPUS:84953234922
SN - 0163-3864
VL - 78
SP - 3041
EP - 3048
JO - Journal of Natural Products
JF - Journal of Natural Products
IS - 12
ER -