Influence of short peptides with aromatic amino acid residues on aggregation properties of serum amyloid A and its fragments

Skibiszewska, Sandra; Żaczek, Szymon; Dybała-Defratyka, Agnieszka; Jędrzejewska, Katarzyna; Jankowska, Elżbieta

doi:10.1016/j.abb.2020.108264

Cited by 10 publications

(10 citation statements)

References 32 publications

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“…However, the overall hydrophobicity of Trp/D-Trp substituted analogs is less than that of des-Phe1 TPF, as estimated by RP-HPLC analysis. We hypothesize that the enhanced assembly seen for Trp/D-Trp substituted analogs might be related to the increased content of aromatic residues, because it could promote the strength of π stacking or cation-π type interaction [ 46 ]. However, the true relation has not been fully clarified so far, and the capability of aromatic moieties to promote aggregation could also be affected by the hydrophobicity, position, and the neighboring side chains in their three-dimensional conformation.…”

Section: Discussionmentioning

confidence: 99%

Aggregation and Its Influence on the Bioactivities of a Novel Antimicrobial Peptide, Temporin-PF, and Its Analogues

Zai

et al. 2021

IJMS

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Temporin is an antimicrobial peptide (AMP) family discovered in the skin secretion of ranid frog that has become a promising alternative for conventional antibiotic therapy. Herein, a novel temporin peptide, Temporin-PF (TPF), was successfully identified from Pelophylax fukienensis. It exhibited potent activity against Gram-positive bacteria, but no effect on Gram-negative bacteria. Additionally, TPF exhibited aggregation effects in different solutions. Three analogs were further designed to study the relationship between the aggregation patterns and bioactivities, and the MD simulation was performed for revealing the pattern of the peptide assembly. As the results showed, all peptides were able to aggregate in the standard culture media and salt solutions, especially CaCl2 and MgCl2 buffers, where the aggregation was affected by the concentration of the salts. MD simulation reported that all peptides were able to form oligomers. The parent peptide assembly depended on the hydrophobic interaction via the residues in the middle domain of the sequence. However, the substitution of Trp/D-Trp resulted in an enhanced inter-peptide interaction in the zipper-like domain and eliminated overall biological activities. Our study suggested that introducing aromaticity at the zipper-like domain for temporin may not improve the bioactivities, which might be related to the formation of aggregates via the inter-peptide contacts at the zipper-like motif domain, and it could reduce the binding affinity to the lipid membrane of microorganisms.

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Section: Discussionmentioning

confidence: 99%

Aggregation and Its Influence on the Bioactivities of a Novel Antimicrobial Peptide, Temporin-PF, and Its Analogues

Zai

et al. 2021

IJMS

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“…These peptides are chosen from the sequence of amyloidogenic proteins for their complementarity to the regions on the SAA protein that are responsible for self-association [9][10][11][12][13] . This peptide-based approach has been successfully applied to combat aggregation of amyloid-β (Aβ) peptides (connected to Alzheimer's disease) and α-synuclein (implied in Parkinson's disease), where sodesigned inhibitors are able to prevent fibril formation and to disaggregate preformed fibrils, both in cell culture models and in animal models [9][10][11][12][13][14][15] . Earlier biophysical studies have confirmed that the N-terminal sequence RSFFS of the SAA protein and the Aβ peptide segment Aβ17-20 (LVFF) can significantly suppress the SAA aggregation process 10 .…”

Section: Introductionmentioning

confidence: 99%

“…However, that study considered as drug target only the short SAA1-12 fragment 16,17 , which has different aggregation propensity than larger segments. 12 For this reason, we choose in the present study assemblies of larger SAA fragments as drug targets, but select again these two peptides as possible drug candidates. In addition, we add as a third inhibitor candidate the peptide FVFLM of the protein SERPINA1, found in in urine and placenta 18 of pregnant women suffering from preeclampsia.…”

Section: Introductionmentioning

confidence: 99%

Small Peptides for Inhibiting Serum Amyloid A Aggregation

Jana

Greenwood

Hansmann

2021

Preprint

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Deposition of human Serum Amyloid A (SAA) amyloids in blood vessels, causing inflammation, thrombosis and eventually organ damage, are a commonly seen as a consequence of certain cancers and inflammatory diseases. Several attempts have been made to develop peptide-based drugs that inhibit or at least slow down SAA amyloidosis. We use extensive all-atom molecular dynamic simulations to compare three of these drug candidates for their ability to destabilize SAA fibrils, and to propose for the best candidate, the N-terminal sequence SAA1-5, a mechanism for inhibition. As the life-time of peptide drugs can be increased by replacing L-amino acids with their mirror D- amino acids, we have also studied corresponding D-peptides. We find that DRI-SAA1-5, formed of D-amino acids with the sequence of the peptide reversed, has similar inhibitory properties than the original L-peptide, and therefore may be a promising candidate for drugs targeting SAA amyloidosis.

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“…These peptides are chosen from the sequence of amyloidogenic proteins for their complementarity to the regions on the SAA protein that are responsible for self-association. − This peptide-based approach has been successfully applied to combat aggregation of amyloid-β (Aβ) peptides (connected to Alzheimer’s disease) and α-synuclein (implied in Parkinson’s disease), where so-designed inhibitors are able to prevent fibril formation and to disaggregate preformed fibrils, both in cell culture models and in animal models. − Earlier biophysical studies have confirmed that the N-terminal sequence RSFFS of the SAA protein (to which we refer in the following as R5S) and the Aβ peptide segment Aβ 17–20 (LVFF), called by us L4F, can significantly suppress the SAA aggregation process . However, that study considered as drug target only the short SAA 1–12 fragment, , which has a different aggregation propensity than larger segments . For this reason, we choose in the present study assemblies of larger SAA fragments as drug targets but select again these two peptides as possible drug candidates.…”

mentioning

confidence: 99%

“…10 However, that study considered as drug target only the short SAA 1−12 fragment, 16,17 which has a different aggregation propensity than larger segments. 12 For this reason, we choose in the present study assemblies of larger SAA fragments as drug targets but select again these two peptides as possible drug candidates. In addition, we add as a third inhibitor candidate the peptide FVFLM of the protein SERPINA1, found in the urine and placenta 18 of pregnant women suffering from preeclampsia.…”

mentioning

confidence: 99%

Small Peptides for Inhibiting Serum Amyloid A Aggregation

Jana

Greenwood

Hansmann

2021

ACS Med. Chem. Lett.

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Deposition of human serum amyloid A (SAA) amyloids in blood vessels, causing inflammation, thrombosis, and eventually organ damage, is commonly seen as a consequence of certain cancers and inflammatory diseases and may also be a risk after SARS-COV-2 infections. Several attempts have been made to develop peptide-based drugs that inhibit or at least slow down SAA amyloidosis. We use extensive all-atom molecular dynamic simulations to compare three of these drug candidates for their ability to destabilize SAA fibrils and to propose for the best candidate, the N-terminal sequence SAA1-5, a mechanism for inhibition. As the lifetime of peptide drugs can be increased by replacing L-amino acids with their mirror D-amino acids, we have also studied corresponding D-peptides. We find that DRI-SAA1-5, formed of D-amino acids with the sequence of the peptide reversed, has similar inhibitory properties compared to the original L-peptide and therefore may be a promising candidate for drugs targeting SAA amyloidosis.

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Influence of short peptides with aromatic amino acid residues on aggregation properties of serum amyloid A and its fragments

Cited by 10 publications

References 32 publications

Aggregation and Its Influence on the Bioactivities of a Novel Antimicrobial Peptide, Temporin-PF, and Its Analogues

Aggregation and Its Influence on the Bioactivities of a Novel Antimicrobial Peptide, Temporin-PF, and Its Analogues

Small Peptides for Inhibiting Serum Amyloid A Aggregation

Small Peptides for Inhibiting Serum Amyloid A Aggregation

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