In Vitro Antiplasmodium Effects of Dermaseptin S4 Derivatives

Abstract

The 13-residue dermaseptin S4 derivative K 4 S4(1-13)a (P) was previously shown to kill intraerythrocytic malaria parasites through the lysis of the host cells. In this study, we have sought peptides that will kill the parasite without lysing the erythrocyte. To produce such peptides, 26 compounds of variable structure and size were attached to the N terminus of P and screened for antiplasmodium and hemolytic activities in cultures of Plasmodium falciparum. Results from this screen indicated that increased hydrophobicity results in amplified antiplasmodium effect, irrespective of the linearity or bulkiness of the additive. However, increased hydrophobicity also was generally associated with increased hemolysis, with the exception of two derivatives: propionyl-P (C3-P) and isobutyryl-P (iC4-P). Both acyl-peptides were more effective than P, with 50% growth inhibition at 3.8, 4.3, and 7.7 M, respectively. The antiparasitic effect was time dependent and totally irreversible, implying a cytotoxic effect. The peptides were also investigated in parallel for their ability to inhibit parasite growth and to induce hemolysis in infected and uninfected erythrocytes. Whereas the dose dependence of growth inhibition and hemolysis of infected cells overlapped when cells were treated with P, the acyl-peptides exerted 50% growth inhibition at concentrations that did not cause hemolysis. Noticeably, the acyl derivatives, but not P, were able to dissipate the parasite plasma membrane potential and cause depletion of intraparasite potassium under nonhemolytic conditions. These results clearly demonstrate that the acyl-peptides can affect parasite viability in a manner that is dissociated from lysis of the host cell. Overall, the data indicate the potential usefulness of this strategy for development of selective peptides as investigative tools and eventually as antimalarial agents.

Direct Interaction of Dermaseptin S4 Aminoheptanoyl Derivative with Intraerythrocytic Malaria Parasite Leading to Increased Specific Antiparasitic Activity in Culture

“…Increasing the lipophilicity of the peptide will render it more permeable through the host cell membrane and therefore more accessible to the parasite membrane. Because this feature also increases hemolytic activity (6,17), we have used aminoacyl moieties to reduce hydrophobicity and, hence, the risk for hemolysis.…”

“…Antimicrobial peptides have recently emerged as interesting tools for exploring new antimalarial targets (2)(3)(4)(5)(6). These ubiquitous peptides vary considerably in structure, size, amino acid sequence, and spectrum of action (7)(8)(9)(10)(11), but the most potent peptides always have a pronounced amphipathic and distinctly basic character (12)(13)(14)(15)(16).…”

“…Although K 4 -S4(1-13) was less hemolytic to normal erythrocytes, it was deemed necessary to develop additional derivatives that could affect the parasite with minimal threat to erythrocytes. Recently, acyl derivatives of K 4 -S4(1-13) were shown to increase antiplasmodial activity, although the most potent antiparasitic peptides still displayed high hemolytic activity (6). In this study, a series of new dermaseptin S4 derivatives based on K 4 -S4(1-13) were produced and investigated for antiplasmodial and hemolytic properties.…”

Antibacterial Properties of Dermaseptin S4 Derivatives under Extreme Incubation Conditions

“…Many are active towards a wide range of microorganisms by a mode of action which is still not fully understood but is assumed to involve interaction with the bacterial membrane and its disruption. AMPs do not require interaction with a chiral center for activity, supporting a lower probability for microorganisms to develop efficient resistance mechanisms compared with conventional antibiotics (22,38).AMPs from the dermaseptin family were recently proposed as model peptides for investigating the effects of acyl conjugation (13,17,44). These amphibian-derived AMPs (35, 36) have been amply investigated during the past decade and shown to exert rapid cytolytic activity against a wide range of microorganisms, including gram-negative and gram-positive bacteria, protozoa, filamentous fungi (14,26,35,36), spores of pathogenic bacteria (29), yeasts (11), and intracellular parasites (13,17,30), as well as antiviral activity (5).…”

New Antimicrobial Hexapeptides: Synthesis, Antimicrobial Activities, Cytotoxicity, and Mechanistic Studies

“…[12] Models proposed to explain the mechanism of microbial cytoplasmic membrane disruption by AMPs include the 'barrel-stave' model, the 'toroid pore' or 'wormhole' model, and the 'carpet' model. [7,[13][14][15] In general, the initial association of AMPs with the microbial membrane occurs Synthetic antimicrobial peptides have recently emerged as promising candidates against drug-resistant pathogens. We identified a novel hexapeptide, Orn-d-Trp-d-Phe-Ile-d-PheHis(1-Bzl)-NH 2 , which exhibits broad-spectrum antifungal and antibacterial activity.…”