The Physical Matrix of the Plasma Membrane as a Target: The Charm of Drugs with Low Specificity

Rivas, Luís; Nachér-Vázquez, Montserrat; Andreu, David

doi:10.1039/9781788010177-00248

Cited by 4 publications

(5 citation statements)

References 205 publications

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“…Nevertheless, infective bacteria, fungi and protozoa are an appealing test for CPP. The cell membrane of these pathogens shows an external anionic hemilayer, in contrast to the zwitterionic one of mammalian cells, privileging interactions of cationic CPP with such pathogens [ 25 ]. Furthermore, pathogenic organisms are frequently endowed with a high proteolytic armamentarium as part of their virulence program [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

Chiral Cyclobutane-Containing Cell-Penetrating Peptides as Selective Vectors for Anti-Leishmania Drug Delivery Systems

Illa

Olivares

Gaztelumendi

et al. 2020

IJMS

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Two series of new hybrid γ/γ-peptides, γ-CC and γ-CT, formed by (1S,2R)-3-amino-2,2,dimethylcyclobutane-1-carboxylic acid joined in alternation to a Nα-functionalized cis- or trans-γ-amino-l-proline derivative, respectively, have been synthesized and evaluated as cell penetrating peptides (CPP) and as selective vectors for anti-Leishmania drug delivery systems (DDS). They lacked cytotoxicity on the tumoral human cell line HeLa with a moderate cell-uptake on these cells. In contrast, both γ-CC and γ-CT tetradecamers were microbicidal on the protozoan parasite Leishmania beyond 25 μM, with significant intracellular accumulation. They were conjugated to fluorescent doxorubicin (Dox) as a standard drug showing toxicity beyond 1 μM, while free Dox was not toxic. Intracellular accumulation was 2.5 higher than with Dox-TAT conjugate (TAT = transactivator of transcription, taken as a standard CPP). The conformational structure of the conjugates was approached both by circular dichroism spectroscopy and molecular dynamics simulations. Altogether, computational calculations predict that the drug-γ-peptide conjugates adopt conformations that bury the Dox moiety into a cavity of the folded peptide, while the positively charged guanidinium groups face the solvent. The favorable charge/hydrophobicity balance in these CPP improves the solubility of Dox in aqueous media, as well as translocation across cell membranes, making them promising candidates for DDS.

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Section: Introductionmentioning

confidence: 99%

Chiral Cyclobutane-Containing Cell-Penetrating Peptides as Selective Vectors for Anti-Leishmania Drug Delivery Systems

Illa

Olivares

Gaztelumendi

et al. 2020

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…Conversely, the membrane of mammalian cells is a bilayer membrane mainly made up of zwitterionic phospholipids and thus has a net neutral charge. Rivas and colleagues described in detail that the composition of the trypanosomatid membrane is made up of negatively charged components, such as phosphatidylcholine, sphingolipids, and sterols [ 27 ]. However, the structure of the membrane and its variations associated with the cell stage of the parasite, as well as whether this influences the interaction with AMPs and/or CPPs, remains to be studied in detail.…”

Section: How Do Amps and Cpps Specifically Target Protozoan Parasites...mentioning

confidence: 99%

Neglected Zoonotic Diseases: Advances in the Development of Cell-Penetrating and Antimicrobial Peptides against Leishmaniosis and Chagas Disease

Robledo,

Pérez-Silanes,

Fernández-Rubio

et al. 2023

Pathogens

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In 2020, the WHO established the road map for neglected tropical diseases 2021–2030, which aims to control and eradicate 20 diseases, including leishmaniosis and Chagas disease. In addition, since 2015, the WHO has been developing a Global Action Plan on Antimicrobial Resistance. In this context, the achievement of innovative strategies as an alternative to replace conventional therapies is a first-order socio-sanitary priority, especially regarding endemic zoonoses in poor regions, such as those caused by Trypanosoma cruzi and Leishmania spp. infections. In this scenario, it is worth highlighting a group of natural peptide molecules (AMPs and CPPs) that are promising strategies for improving therapeutic efficacy against these neglected zoonoses, as they avoid the development of toxicity and resistance of conventional treatments. This review presents the novelties of these peptide molecules and their ability to cross a whole system of cell membranes as well as stimulate host immune defenses or even serve as vectors of molecules. The efforts of the biotechnological sector will make it possible to overcome the limitations of antimicrobial peptides through encapsulation and functionalization methods to obtain approval for these treatments to be used in clinical programs for the eradication of leishmaniosis and Chagas disease.

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“…Conversely, the membrane of mammalian cells is characterized by being a bilayer mainly made up of zwitterionic phospholipids, and therefore with a net neutral charge. Rivas and colleagues described in detail that the composition of the trypanosomatid membrane is made up of negatively charged components such as phosphatidylcholine, sphingolipids, and sterols [25]. However, the structure of the membrane and its variations associated with the cell stage of the parasite remains to be studied in detail, as well as if this influences the interaction with AMPs and/or CPPs.…”

Section: How Do Amps and Cpps Specifically Target Protozoan Parasites...mentioning

confidence: 99%

Neglected Zoonotic Diseases: Advances in the Development of Cell-Penetrating and Antimicrobial Peptides against Leishmaniosis and Chagas

Robledo,

Pérez-Silanes,

Fernández-Rubio

et al. 2023

Preprint

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In 2020, the WHO established a road map for neglected tropical diseases 2021−2030 that aims to control and eradicate 20 diseases, including Leishmaniosis and Chagas disease. In addition, since 2015, the WHO has been developing a Global Action Plan on Antimicrobial Resistance. In this context, the achievement of innovative strategies as an alternative to replace conventional therapies is a first-order socio-sanitary priority, especially regarding endemic zoonoses in poor regions such as those caused by Trypanosoma cruzi and Leishmania spp infections. In this scenario, it is worth highlighting a group of natural peptide molecules (AMPs and CPPs) that are promising strategies for improving therapeutic efficacy against these neglected zoonoses, avoiding the development of toxicity and resistance of conventional treatments. This review presents the novelties of these peptide molecules and their ability to cross a whole system of cell membranes, as well as to stimulate the host immune defenses or even serve as a vector of molecules. The efforts of the biotechnological sector will make it possible to overcome the limitations of antimicrobial peptides through encapsulation and functionalization methods to obtain approval for these treatments to be used in clinical programs for the eradication of Leishmaniosis and Chagas disease.

show abstract

The Physical Matrix of the Plasma Membrane as a Target: The Charm of Drugs with Low Specificity

Cited by 4 publications

References 205 publications

Chiral Cyclobutane-Containing Cell-Penetrating Peptides as Selective Vectors for Anti-Leishmania Drug Delivery Systems

Chiral Cyclobutane-Containing Cell-Penetrating Peptides as Selective Vectors for Anti-Leishmania Drug Delivery Systems

Neglected Zoonotic Diseases: Advances in the Development of Cell-Penetrating and Antimicrobial Peptides against Leishmaniosis and Chagas Disease

Neglected Zoonotic Diseases: Advances in the Development of Cell-Penetrating and Antimicrobial Peptides against Leishmaniosis and Chagas

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