Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 3 de 3
Add filters

Document Type
Year range
J Phys Chem B ; 126(20): 3648-3658, 2022 05 26.
Article in English | MEDLINE | ID: covidwho-1947182


Aggregates of α-synuclein are thought to be the disease-causing agent in Parkinson's disease. Various case studies have hinted at a correlation between COVID-19 and the onset of Parkinson's disease. For this reason, we use molecular dynamics simulations to study whether amyloidogenic regions in SARS-COV-2 proteins can initiate and modulate aggregation of α-synuclein. As an example, we choose the nine-residue fragment SFYVYSRVK (SK9), located on the C-terminal of the envelope protein of SARS-COV-2. We probe how the presence of SK9 affects the conformational ensemble of α-synuclein monomers and the stability of two resolved fibril polymorphs. We find that the viral protein fragment SK9 may alter α-synuclein amyloid formation by shifting the ensemble toward aggregation-prone and preferentially rod-like fibril seeding conformations. However, SK9 has only a small effect on the stability of pre-existing or newly formed fibrils. A potential mechanism and key residues for potential virus-induced amyloid formation are described.

Amyloidogenic Proteins , Coronavirus Envelope Proteins , Parkinson Disease , Peptide Fragments , alpha-Synuclein , Amyloidogenic Proteins/chemistry , Amyloidogenic Proteins/metabolism , COVID-19/virology , Coronavirus Envelope Proteins/chemistry , Coronavirus Envelope Proteins/metabolism , Humans , Parkinson Disease/metabolism , Peptide Fragments/chemistry , Peptide Fragments/metabolism , SARS-CoV-2/metabolism , alpha-Synuclein/chemistry , alpha-Synuclein/metabolism
ACS Med Chem Lett ; 12(10): 1613-1621, 2021 Oct 14.
Article in English | MEDLINE | ID: covidwho-1483085


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.

J Phys Chem B ; 125(32): 9155-9167, 2021 08 19.
Article in English | MEDLINE | ID: covidwho-1347913


A marker for the severeness and disease progress of COVID-19 is overexpression of serum amyloid A (SAA) to levels that in other diseases are associated with a risk for SAA amyloidosis. To understand whether SAA amyloidosis could also be a long-term risk of SARS-CoV-2 infections, we have used long all-atom molecular dynamic simulations to study the effect of a SARS-CoV-2 protein segment on SAA amyloid formation. Sampling over 40 µs, we find that the presence of the nine-residue segment SK9, located at the C-terminus of the envelope protein, increases the propensity for SAA fibril formation by three mechanisms: it reduces the stability of the lipid-transporting hexamer shifting the equilibrium toward monomers, it increases the frequency of aggregation-prone configurations in the resulting chains, and it raises the stability of SAA fibrils. Our results therefore suggest that SAA amyloidosis and related pathologies may be a long-term risk of SARS-CoV-2 infections.

Amyloidosis , COVID-19 , Amyloid , Humans , SARS-CoV-2 , Serum Amyloid A Protein