Infectious diseases caused by microbial pathogens (bacteria, virus, fungi, parasites) claim milli... more Infectious diseases caused by microbial pathogens (bacteria, virus, fungi, parasites) claim millions of deaths per year worldwide and have become a serious challenge to global human health in our century. Viral infections are particularly notable in this regard, not only because humankind is facing some of the deadliest viral pandemics in recent history, but also because the arsenal of drugs to combat the high levels of mutation, and hence the antigenic variability of (mostly RNA) viruses, is disturbingly scarce. Therefore, the search for new antivirals able to successfully fight infection with minimal or no adverse effects on the host is a pressing task. Traditionally, antiviral therapies have relied on relatively small-sized drugs acting as proteases, polymerases, integrase inhibitors, etc. In recent decades, novel approaches involving targeted delivery such as that achieved by peptide–drug conjugates (PDCs) have gained attention as alternative (pro)drugs for tackling viral diseas...
Proteolytic stability assessment is increasingly viewed as a fundamental component of peptide cha... more Proteolytic stability assessment is increasingly viewed as a fundamental component of peptide characterization, arguably of comparable importance as efficacy and toxicity data. A literature survey over the last decade reveals steady growth in the stability information available. However, it also uncovers two significant problems that hinder proper data comparison: 1) the use of different stability assays, and 2) the differences in how stability information is reported. In this Viewpoint, we present results from a database metaanalysis as well as concerns about the stability assessments published so far. We also suggest guidelines for a proper discussion between experts in the field on how to improve data readability so that peptide stability, an often-missing parameter in older literature, is adequately reported to take maximum advantage of it.
G-protein-coupled receptors associate into dimers/oligomers whose function is not well understood... more G-protein-coupled receptors associate into dimers/oligomers whose function is not well understood. One approach to investigate this issue is to challenge oligomerization by peptides replicating transmembrane domains and to study their effect on receptor functionality. The disruptor peptides are typically delivered by means of cell-penetrating vectors such as the human immunodeficiency virus (HIV) transcription trans-activation protein Tat. In this paper we report a cyclic, Tat-like peptide that significantly improves its linear analogue in targeting interreceptor sequences in the transmembrane space. The same cyclic Tat-like vector fused to a transmembrane region not involved in receptor oligomerization was totally ineffective. Besides higher efficacy, the cyclic version has enhanced proteolytic stability, as shown by trypsin digestion experiments.
BacWound: The MUC2 intestinal mucin gene contains tandem repeats of 23 amino acid length that are... more BacWound: The MUC2 intestinal mucin gene contains tandem repeats of 23 amino acid length that are rich in threonine. Methods: Mouse monoclonai antibody LDQlO was raised against chemically degiycosyiated mucin isolated from LS174T colon cancer nude mouse xenografts. Results: LDQlO reacts with degiycosylated colon cancer mucin and with a synthetic peptide encompassing the MUC2 tandem repeat sequence. in immunohistochemicai assays, strong reactivity with goblet ceils in colon, small bowel, and stomach is observed; weaker reactivity with mucin-producing ceils in other epitheiiai tissues is shown. The epitope recognized by LDQlO is localized in the rough endopiasmic reticulum of normal colonic goblet ceils. LDQlO also shows strong reactivity with coiorectai and stomach cancers and weaker reactivity with pancreas, breast, and bladder cancers. Conclusions: Antibody LDQlO detects a peptide epitope of MUC2 that becomes cryptic on giycosyiation. Altered synthesis of the MUC2 apomucin takes place in a variety of epitheiiai cancers.
ST-segment elevation myocardial infarction (STEMI) triggers remote extracellular matrix expansion... more ST-segment elevation myocardial infarction (STEMI) triggers remote extracellular matrix expansion. Myocardial extracellular volume fraction (ECV), determined by cardiovascular magnetic resonance, permits quantification of interstitial space expansion. Our aim was to determine the relationship between early serum fibrosis biomarkers and 180-day post-infarct remote myocardium remodeling using ECV. In 26 patients with STEMI, functional imaging, T1-mapping, and late-gadolinium-enhancement were performed on a 3-T CMR scanner at baseline (days 3 to 5) and 180days. Biomarkers were measured at days 1, 3, and 7 after STEMI. The mean initial and follow-up left ventricular ejection fraction (LVEF) were 48.3±18.1% and 52.6±12.3%, respectively. Initial infarct size was 11.6±16.8% of LV mass. ECV in the remote myocardium at 180days correlated with indexed end-systolic volume (r=0.4, p=0.045). A significant correlation was observed between galectin-3 at day 7 and ECV at 6months (r=0.428, p=0.037). A trend towards a direct correlation was found for BNP (r=0.380, p=0.059). Multivariate analysis revealed that BNP and galectin-3 were independent predictors of long-term changes in ECV and explained nearly 30% of the variance in this parameter (r(2)=0.34; p=0.01). A galectin-3 cutoff value of 10.15ng/mL was the most powerful predictor of high ECV values (≥28.5%) at follow-up. Galectin-3 at day 7 was an independent predictor of high ECV values at follow-up (OR=22.51; CI 95%: 2.1-240.72; p=0.01) with 0.76 AUC (CI: 0.574-0.964; p=0.03). Galectin-3 measured acutely after STEMI is an independent predictor of increased ECV at 6-month follow-up that might be useful for long-term risk stratification.
A 2l-residue, two disulfidecontaining peptide has been synthesized on solid phase. Three alternat... more A 2l-residue, two disulfidecontaining peptide has been synthesized on solid phase. Three alternative protection schemes, based on Boclbenzyl chemistry and combinations of the 4-methylbenzyl with either acetamidomethyl, 9-fluorenylmethyl or 3-nitro-2pyridylsulfenyl groups for pairs of cysteine residues have been examined. The most successful route involved formation of the first disulfide on the resin via 9-fluorenylmethylcysteine deprotection-oxidation.
Formation of an asymmetric disulfide bridge between two peptide chains is often one of the most p... more Formation of an asymmetric disulfide bridge between two peptide chains is often one of the most problematic aspects of peptide ~ynthesis.~ Since cooxidation of two cysteine-containing peptides gives mixtures of homo-and heterodimers, directed methods for the formation of heterodisulfides are r e q~i r e d .~ A
Methyl tert-butyl ether (MTBE) and diethyl ether (DEE) tend to be regarded as interchangeable for... more Methyl tert-butyl ether (MTBE) and diethyl ether (DEE) tend to be regarded as interchangeable for the 'cold ether' workup concluding the final acidolytic cleavage and deprotection step of solid-phase peptide syntheses. However, the use of MTBE to precipitate peptides from strong acid solutions is shown to give rise to t-butyl alkylation byproducts, readily detectable by MALDI-TOF MS. The problem can attain undesirable dimensions in the cleavage of peptide resins containing high proportions of aromatic residues, particularly in peptide nucleic acid (PNA) syntheses. In those cases, DEE workup is advisable, as it consistently leads to cleaner products.
Foot-and-mouth disease virus (FMDV) of serotype C (isolate C-S8c1) was cleaved in situ by trypsin... more Foot-and-mouth disease virus (FMDV) of serotype C (isolate C-S8c1) was cleaved in situ by trypsin at the Arg-Gly-Asp (RGD) motif, which is involved both in attachment of FMDV to cells and in recognition of a major antigenic site (site A) by antibodies. Though 99.4% of the RGD moieties were cleaved, the virus remained infectious. A synthetic peptide which represented the sequence of the VP1 G-H loop of C-S8c1, including the RGD motif, greatly inhibited FMDV attachment to cells. The same peptide inhibited, very effectively and to the same extent (50% inhibition at about 1 microM), the infectivity of both intact and trypsin-treated virus. Replacement of Asp with Glu at the RGD motif abolished the inhibitory effects of the peptide. Thus, the RGD motif is involved in the infectivity of both intact and RGD-cleaved serotype C FMDV. Trypsin treatment did not affect the reactivity of the virus with some monoclonal antibodies (MAbs) directed to site A whose epitopes involve mainly residues contiguous to the cleaved bond, but diminished the reactivity with site A MAbs whose epitopes include the RGD sequence and flanking residues. However, high concentrations of any site A MAb tested neutralized close to 100% of the infectious trypsin-treated virus. We propose that, in spite of covalent cleavage, the high number of intramolecular non-covalent interactions observed within the G-H loop of FMDV C-S8c1 (complexed to antibody) may hold the RGD in a nearly correct conformation and allow--albeit with reduced affinity--antibody and cell receptor recognition of RGD-cleaved FMDV.
Interactions between peptides and DNA can be followed by observing the chemical shift changes of ... more Interactions between peptides and DNA can be followed by observing the chemical shift changes of the tyrosine and histidine side chain protons in the presence of DNA. These changes are often interpreted as arising from the diamagnetic anisotropy of the aromatic bases of DNA. In the case of histidine the change of the pK, of the imidazole side chain caused by the proximity of the negatively charged DNA is an alternative explanation for the observed shifts. A distinction between these two effects in the complexes of histidinamide and Ac-His-Arg-Tyr-Arg-P-OH with DNA is made by recording the spectra over the complete titration curve. The observed shifts can be treated semiquantitatively using the Gouy-Chapman theory. o 198s Academic PKSS, IIIC.
A novel approach to the preparation of immunopeptide-carrier protein conjugates of improved chemi... more A novel approach to the preparation of immunopeptide-carrier protein conjugates of improved chemical definition based on a solid-phase synthetic protocol combining incorporation of a Cys(Npys) N-terminal residue with systematic acetylation after every coupling, is described. The potential of the method is demonstrated in a synthesis of the tridecapeptide (Npys)-Cys-Val-Asn-Tyr-Ile-Arg-Lys-Arg-Ser-Leu-Gln-Thr-Val-OH in which the main product is purposely contaminated by a number of shorter truncated sequences resulting from intentionally defective couplings. From this peptide crude, and rather independently of its complexity, the target sequence can be selectively recovered and attached to a carrier molecule through a disulfide bond formed by reaction of the Npys-protected cysteine residue and a thiol function in the carrier. The process can be properly named purification-by-conjugation.
International journal of biological macromolecules, Jan 19, 2017
In this work we report the production of cellulose nanopapers modified with alkyl ketene dimer (A... more In this work we report the production of cellulose nanopapers modified with alkyl ketene dimer (AKD) in order to allow the immobilization of antimicrobial peptides (AMPs) to produce surfaces with antimicrobial properties. Cellulose nanofibers (CNF) were prepared from softwood bleached pulp via high pressure homogenization after chemical pretreatment of fibers via TEMPO oxidation. Nanopapers were then prepared after a casting technique and functionalized with alkyl ketene dimer before AMPs were immobilized. The immobilization process was performed by submerging the samples into AMP aqueous solutions and then dried at room temperature. Antimicrobial activity was tested against B. subtilis. Results indicated that AMPs were bound onto the nanopaper surface and released when the nanopaper was put in contact with the culture medium, which effectively demonstrates the viability of the immobilization process.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-... more This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
G protein-coupled receptors (GPCRs) are a superfamily of proteins classically described as monome... more G protein-coupled receptors (GPCRs) are a superfamily of proteins classically described as monomeric transmembrane (TM) receptors. However, increasing evidence indicates that many GPCRs form higher-order assemblies made up of monomers pertaining to identical (homo) or to various (hetero) receptors. The formation and structure of these oligomers, their physiological role and possible therapeutic applications raise a variety of issues that are currently being actively explored. In this context, synthetic peptides derived from TM domains stand out as powerful tools that can be predictably targeted to disrupt GPCR oligomers, especially at the interface level, eventually impairing their action. However, despite such potential, TM-derived, GPCR-disrupting peptides often suffer from inadequate pharmacokinetic properties, such as low bioavailability, a short half-life or rapid clearance, which put into question their therapeutic relevance and promise. In this review, we provide a comprehens...
Conjugation of TP10, a cell-penetrating peptide with intrinsic antimalarial activity, to the well... more Conjugation of TP10, a cell-penetrating peptide with intrinsic antimalarial activity, to the well-known antimalarial drugs chloroquine and primaquine has been previously shown to enhance the peptide’s action against, respectively, blood- and liver-stage malaria parasites. Yet, this was achieved at the cost of a significant increase in haemolytic activity, as fluorescence microscopy and flow cytometry studies showed the conjugates to be more haemolytic for non-infected than for Plasmodium-infected red blood cells. To gain further insight into how these conjugates distinctively bind, and likely disrupt, membranes of both Plasmodium-infected and non-infected erythrocytes, we used dynamic light scattering and surface plasmon resonance to study the interactions of two representative conjugates and their parent compounds with lipid model membranes. Results obtained are herein reported and confirm that a strong membrane-disruptive character underlies the haemolytic properties of these conj...
Infectious diseases caused by microbial pathogens (bacteria, virus, fungi, parasites) claim milli... more Infectious diseases caused by microbial pathogens (bacteria, virus, fungi, parasites) claim millions of deaths per year worldwide and have become a serious challenge to global human health in our century. Viral infections are particularly notable in this regard, not only because humankind is facing some of the deadliest viral pandemics in recent history, but also because the arsenal of drugs to combat the high levels of mutation, and hence the antigenic variability of (mostly RNA) viruses, is disturbingly scarce. Therefore, the search for new antivirals able to successfully fight infection with minimal or no adverse effects on the host is a pressing task. Traditionally, antiviral therapies have relied on relatively small-sized drugs acting as proteases, polymerases, integrase inhibitors, etc. In recent decades, novel approaches involving targeted delivery such as that achieved by peptide–drug conjugates (PDCs) have gained attention as alternative (pro)drugs for tackling viral diseas...
Proteolytic stability assessment is increasingly viewed as a fundamental component of peptide cha... more Proteolytic stability assessment is increasingly viewed as a fundamental component of peptide characterization, arguably of comparable importance as efficacy and toxicity data. A literature survey over the last decade reveals steady growth in the stability information available. However, it also uncovers two significant problems that hinder proper data comparison: 1) the use of different stability assays, and 2) the differences in how stability information is reported. In this Viewpoint, we present results from a database metaanalysis as well as concerns about the stability assessments published so far. We also suggest guidelines for a proper discussion between experts in the field on how to improve data readability so that peptide stability, an often-missing parameter in older literature, is adequately reported to take maximum advantage of it.
G-protein-coupled receptors associate into dimers/oligomers whose function is not well understood... more G-protein-coupled receptors associate into dimers/oligomers whose function is not well understood. One approach to investigate this issue is to challenge oligomerization by peptides replicating transmembrane domains and to study their effect on receptor functionality. The disruptor peptides are typically delivered by means of cell-penetrating vectors such as the human immunodeficiency virus (HIV) transcription trans-activation protein Tat. In this paper we report a cyclic, Tat-like peptide that significantly improves its linear analogue in targeting interreceptor sequences in the transmembrane space. The same cyclic Tat-like vector fused to a transmembrane region not involved in receptor oligomerization was totally ineffective. Besides higher efficacy, the cyclic version has enhanced proteolytic stability, as shown by trypsin digestion experiments.
BacWound: The MUC2 intestinal mucin gene contains tandem repeats of 23 amino acid length that are... more BacWound: The MUC2 intestinal mucin gene contains tandem repeats of 23 amino acid length that are rich in threonine. Methods: Mouse monoclonai antibody LDQlO was raised against chemically degiycosyiated mucin isolated from LS174T colon cancer nude mouse xenografts. Results: LDQlO reacts with degiycosylated colon cancer mucin and with a synthetic peptide encompassing the MUC2 tandem repeat sequence. in immunohistochemicai assays, strong reactivity with goblet ceils in colon, small bowel, and stomach is observed; weaker reactivity with mucin-producing ceils in other epitheiiai tissues is shown. The epitope recognized by LDQlO is localized in the rough endopiasmic reticulum of normal colonic goblet ceils. LDQlO also shows strong reactivity with coiorectai and stomach cancers and weaker reactivity with pancreas, breast, and bladder cancers. Conclusions: Antibody LDQlO detects a peptide epitope of MUC2 that becomes cryptic on giycosyiation. Altered synthesis of the MUC2 apomucin takes place in a variety of epitheiiai cancers.
ST-segment elevation myocardial infarction (STEMI) triggers remote extracellular matrix expansion... more ST-segment elevation myocardial infarction (STEMI) triggers remote extracellular matrix expansion. Myocardial extracellular volume fraction (ECV), determined by cardiovascular magnetic resonance, permits quantification of interstitial space expansion. Our aim was to determine the relationship between early serum fibrosis biomarkers and 180-day post-infarct remote myocardium remodeling using ECV. In 26 patients with STEMI, functional imaging, T1-mapping, and late-gadolinium-enhancement were performed on a 3-T CMR scanner at baseline (days 3 to 5) and 180days. Biomarkers were measured at days 1, 3, and 7 after STEMI. The mean initial and follow-up left ventricular ejection fraction (LVEF) were 48.3±18.1% and 52.6±12.3%, respectively. Initial infarct size was 11.6±16.8% of LV mass. ECV in the remote myocardium at 180days correlated with indexed end-systolic volume (r=0.4, p=0.045). A significant correlation was observed between galectin-3 at day 7 and ECV at 6months (r=0.428, p=0.037). A trend towards a direct correlation was found for BNP (r=0.380, p=0.059). Multivariate analysis revealed that BNP and galectin-3 were independent predictors of long-term changes in ECV and explained nearly 30% of the variance in this parameter (r(2)=0.34; p=0.01). A galectin-3 cutoff value of 10.15ng/mL was the most powerful predictor of high ECV values (≥28.5%) at follow-up. Galectin-3 at day 7 was an independent predictor of high ECV values at follow-up (OR=22.51; CI 95%: 2.1-240.72; p=0.01) with 0.76 AUC (CI: 0.574-0.964; p=0.03). Galectin-3 measured acutely after STEMI is an independent predictor of increased ECV at 6-month follow-up that might be useful for long-term risk stratification.
A 2l-residue, two disulfidecontaining peptide has been synthesized on solid phase. Three alternat... more A 2l-residue, two disulfidecontaining peptide has been synthesized on solid phase. Three alternative protection schemes, based on Boclbenzyl chemistry and combinations of the 4-methylbenzyl with either acetamidomethyl, 9-fluorenylmethyl or 3-nitro-2pyridylsulfenyl groups for pairs of cysteine residues have been examined. The most successful route involved formation of the first disulfide on the resin via 9-fluorenylmethylcysteine deprotection-oxidation.
Formation of an asymmetric disulfide bridge between two peptide chains is often one of the most p... more Formation of an asymmetric disulfide bridge between two peptide chains is often one of the most problematic aspects of peptide ~ynthesis.~ Since cooxidation of two cysteine-containing peptides gives mixtures of homo-and heterodimers, directed methods for the formation of heterodisulfides are r e q~i r e d .~ A
Methyl tert-butyl ether (MTBE) and diethyl ether (DEE) tend to be regarded as interchangeable for... more Methyl tert-butyl ether (MTBE) and diethyl ether (DEE) tend to be regarded as interchangeable for the 'cold ether' workup concluding the final acidolytic cleavage and deprotection step of solid-phase peptide syntheses. However, the use of MTBE to precipitate peptides from strong acid solutions is shown to give rise to t-butyl alkylation byproducts, readily detectable by MALDI-TOF MS. The problem can attain undesirable dimensions in the cleavage of peptide resins containing high proportions of aromatic residues, particularly in peptide nucleic acid (PNA) syntheses. In those cases, DEE workup is advisable, as it consistently leads to cleaner products.
Foot-and-mouth disease virus (FMDV) of serotype C (isolate C-S8c1) was cleaved in situ by trypsin... more Foot-and-mouth disease virus (FMDV) of serotype C (isolate C-S8c1) was cleaved in situ by trypsin at the Arg-Gly-Asp (RGD) motif, which is involved both in attachment of FMDV to cells and in recognition of a major antigenic site (site A) by antibodies. Though 99.4% of the RGD moieties were cleaved, the virus remained infectious. A synthetic peptide which represented the sequence of the VP1 G-H loop of C-S8c1, including the RGD motif, greatly inhibited FMDV attachment to cells. The same peptide inhibited, very effectively and to the same extent (50% inhibition at about 1 microM), the infectivity of both intact and trypsin-treated virus. Replacement of Asp with Glu at the RGD motif abolished the inhibitory effects of the peptide. Thus, the RGD motif is involved in the infectivity of both intact and RGD-cleaved serotype C FMDV. Trypsin treatment did not affect the reactivity of the virus with some monoclonal antibodies (MAbs) directed to site A whose epitopes involve mainly residues contiguous to the cleaved bond, but diminished the reactivity with site A MAbs whose epitopes include the RGD sequence and flanking residues. However, high concentrations of any site A MAb tested neutralized close to 100% of the infectious trypsin-treated virus. We propose that, in spite of covalent cleavage, the high number of intramolecular non-covalent interactions observed within the G-H loop of FMDV C-S8c1 (complexed to antibody) may hold the RGD in a nearly correct conformation and allow--albeit with reduced affinity--antibody and cell receptor recognition of RGD-cleaved FMDV.
Interactions between peptides and DNA can be followed by observing the chemical shift changes of ... more Interactions between peptides and DNA can be followed by observing the chemical shift changes of the tyrosine and histidine side chain protons in the presence of DNA. These changes are often interpreted as arising from the diamagnetic anisotropy of the aromatic bases of DNA. In the case of histidine the change of the pK, of the imidazole side chain caused by the proximity of the negatively charged DNA is an alternative explanation for the observed shifts. A distinction between these two effects in the complexes of histidinamide and Ac-His-Arg-Tyr-Arg-P-OH with DNA is made by recording the spectra over the complete titration curve. The observed shifts can be treated semiquantitatively using the Gouy-Chapman theory. o 198s Academic PKSS, IIIC.
A novel approach to the preparation of immunopeptide-carrier protein conjugates of improved chemi... more A novel approach to the preparation of immunopeptide-carrier protein conjugates of improved chemical definition based on a solid-phase synthetic protocol combining incorporation of a Cys(Npys) N-terminal residue with systematic acetylation after every coupling, is described. The potential of the method is demonstrated in a synthesis of the tridecapeptide (Npys)-Cys-Val-Asn-Tyr-Ile-Arg-Lys-Arg-Ser-Leu-Gln-Thr-Val-OH in which the main product is purposely contaminated by a number of shorter truncated sequences resulting from intentionally defective couplings. From this peptide crude, and rather independently of its complexity, the target sequence can be selectively recovered and attached to a carrier molecule through a disulfide bond formed by reaction of the Npys-protected cysteine residue and a thiol function in the carrier. The process can be properly named purification-by-conjugation.
International journal of biological macromolecules, Jan 19, 2017
In this work we report the production of cellulose nanopapers modified with alkyl ketene dimer (A... more In this work we report the production of cellulose nanopapers modified with alkyl ketene dimer (AKD) in order to allow the immobilization of antimicrobial peptides (AMPs) to produce surfaces with antimicrobial properties. Cellulose nanofibers (CNF) were prepared from softwood bleached pulp via high pressure homogenization after chemical pretreatment of fibers via TEMPO oxidation. Nanopapers were then prepared after a casting technique and functionalized with alkyl ketene dimer before AMPs were immobilized. The immobilization process was performed by submerging the samples into AMP aqueous solutions and then dried at room temperature. Antimicrobial activity was tested against B. subtilis. Results indicated that AMPs were bound onto the nanopaper surface and released when the nanopaper was put in contact with the culture medium, which effectively demonstrates the viability of the immobilization process.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-... more This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
G protein-coupled receptors (GPCRs) are a superfamily of proteins classically described as monome... more G protein-coupled receptors (GPCRs) are a superfamily of proteins classically described as monomeric transmembrane (TM) receptors. However, increasing evidence indicates that many GPCRs form higher-order assemblies made up of monomers pertaining to identical (homo) or to various (hetero) receptors. The formation and structure of these oligomers, their physiological role and possible therapeutic applications raise a variety of issues that are currently being actively explored. In this context, synthetic peptides derived from TM domains stand out as powerful tools that can be predictably targeted to disrupt GPCR oligomers, especially at the interface level, eventually impairing their action. However, despite such potential, TM-derived, GPCR-disrupting peptides often suffer from inadequate pharmacokinetic properties, such as low bioavailability, a short half-life or rapid clearance, which put into question their therapeutic relevance and promise. In this review, we provide a comprehens...
Conjugation of TP10, a cell-penetrating peptide with intrinsic antimalarial activity, to the well... more Conjugation of TP10, a cell-penetrating peptide with intrinsic antimalarial activity, to the well-known antimalarial drugs chloroquine and primaquine has been previously shown to enhance the peptide’s action against, respectively, blood- and liver-stage malaria parasites. Yet, this was achieved at the cost of a significant increase in haemolytic activity, as fluorescence microscopy and flow cytometry studies showed the conjugates to be more haemolytic for non-infected than for Plasmodium-infected red blood cells. To gain further insight into how these conjugates distinctively bind, and likely disrupt, membranes of both Plasmodium-infected and non-infected erythrocytes, we used dynamic light scattering and surface plasmon resonance to study the interactions of two representative conjugates and their parent compounds with lipid model membranes. Results obtained are herein reported and confirm that a strong membrane-disruptive character underlies the haemolytic properties of these conj...
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