Naslov
Design principles for peptide antibiotics and toxins

Autori
Juretić, D. ; Vukičević, D. ; Bojović, V. ; Ilić, N. ; Lučić, B.

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
From Solid State to Biophysics, 4-th conference, Cavtat, Croatia, June 2008 / - , 2008

Skup
From Solid State to Biophysics, 4-th conference

Mjesto i datum
Cavtat, Hrvatska, 06.06.2008. - 13.06.2008

Vrsta sudjelovanja
Pozvano predavanje

Vrsta recenzije
Nije recenziran

Ključne riječi
peptide antibiotics; design principles

Sažetak
Natural peptide antibiotics produced by many different species are attracting ever greater interest due to almost endless possibilities for minimal changes in their sequence which can produce large increase in their therapeutic index. Different bacterial strains resistant to conventional antibiotics can not develop as easily the resistance to peptide antibiotics due to their generalized primary target of action – specific lipid composition and bioenergetics of bacterial cytoplasmic membrane. However, toxic action of antimicrobial peptides is also quite common when human cells are exposed to them. Our first goal was to design the algorithm capable of distinguishing peptide toxins from peptide antibiotics. This was accomplished for alpha-class linear peptides isolated from different frog species by using the sequence profile of preferences for membrane buried helices (specific preference functions) and sequence profile of hydrophobic moments in addition to frequencies of amino acid residues found more often in antibiotics. Peptides with strong hemolytic action (toxins with low therapeutic index) had high preference to enter deeper into membrane and even to form transmembrane helix, while sequence profiles for antibiotics suggested that they preferred remaining attached to membrane surface with occasional brief entrance deeper into membrane only after their dimmers and “ rafts” formed due to high enough peptide concentration. Our second goal was to design an algorithm capable of accurate prediction for the increase in the therapeutic index (TI) after minimal suggested changes in peptide structure (point mutations). At the same time we wanted this algorithm to be of enough general nature to be able to separate excellent from average amphibian-type antibiotics. With some novel design principles we achieved the correlation r = - 0.893 with experimentally measured values of TI for 37 nonhomologous natural antimicrobial peptides. The coefficient of determination was also good for the test set of 37 natural and synthetic analogues of amphibian peptides ( r = 0.797). The on-line server for predicting the TI of given antimicrobial peptides, for suggesting best point mutation to increase TI and for suggesting the design of novel peptides with high TI is under construction. The experiments for testing peptides designed by using this server are also initiated.

Izvorni jezik
Engleski

Znanstvena područja
Matematika, Fizika, Biologija

POVEZANOST RADA