Trypanothione reductase inhibition and anti-leishmanial activity of all-hydrocarbon stapled α-helical peptides with improved proteolytic stability

Helical peptides stabilizedviaall-hydrocarbon or lactam side-chain bridging were investigated as disruptors ofLeishmania infantumtrypanothione reductase.

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Impact of Dehydroamino Acids on the Structure and Stability of Incipient 3₁₀ Helical Peptides

10.26434/chemrxiv.9968375.v1 ◽

2019 ◽

Author(s):

Daniel Joaquin ◽

Michael A. Lee ◽

David W. Kastner ◽

Jatinder Singh ◽

Shardon T. Morrill ◽

...

Keyword(s):

Room Temperature ◽

Bioactive Peptides ◽

Elevated Temperatures ◽

Peptide Structure ◽

Helical Peptides ◽

Dehydroamino Acids ◽

Structure And Stability ◽

Helical Peptide ◽

Proteolytic Stability ◽

The Impact

<div>A comparative study of the impact of small, medium-sized, and bulky Δ,Δ-dehydroamino acids (ΔAAs) on the structure and stability of Balaram’s incipient 3₁₀ -helical peptide (1) is reported. Replacement of the N-terminal Aib residue of 1 with a ΔAA afforded peptides 2a–c that maintained the 310-helical shape of 1 in solution. In contrast, installation of a ΔAA in place of Aib-3 yielded peptides 3a–c that preferred a Δ-sheet-like conformation. The impact of the ΔAA on peptide structure was independent of size, with small (ΔAla), medium-sized (Z-ΔAbu), and bulky (ΔVal) ΔAAs exerting similar effects. The proteolytic stabilities of 1 and its analogs were determined by incubation with Pronase. Z-ΔAbu and ΔVal increased the resistance of peptides to proteolysis when incorporated at the 3-position and had negligible impact on stability when placed at the 1-position, whereas ΔAla-containing peptides degraded rapidly regardless of position. Exposure of peptides 2a–c and 3a–c to the reactive thiol cysteamine revealed that ΔAla-containing peptides underwent conjugate addition at room temperature, while Z-ΔAbu- and ΔVal-containing peptides were inert even at elevated temperatures. These results suggest that both bulky and the more synthetically accessible medium-sized ΔAAs should be valuable tools for bestowing rigidity and proteolytic stability on bioactive peptides.</div>

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Impact of Dehydroamino Acids on the Structure and Stability of Incipient 3₁₀ Helical Peptides

10.26434/chemrxiv.9968375 ◽

2019 ◽

Author(s):

Daniel Joaquin ◽

Michael A. Lee ◽

David W. Kastner ◽

Jatinder Singh ◽

Shardon T. Morrill ◽

...

Keyword(s):

Room Temperature ◽

Bioactive Peptides ◽

Elevated Temperatures ◽

Peptide Structure ◽

Helical Peptides ◽

Dehydroamino Acids ◽

Structure And Stability ◽

Helical Peptide ◽

Proteolytic Stability ◽

The Impact

<div>A comparative study of the impact of small, medium-sized, and bulky Δ,Δ-dehydroamino acids (ΔAAs) on the structure and stability of Balaram’s incipient 3₁₀ -helical peptide (1) is reported. Replacement of the N-terminal Aib residue of 1 with a ΔAA afforded peptides 2a–c that maintained the 310-helical shape of 1 in solution. In contrast, installation of a ΔAA in place of Aib-3 yielded peptides 3a–c that preferred a Δ-sheet-like conformation. The impact of the ΔAA on peptide structure was independent of size, with small (ΔAla), medium-sized (Z-ΔAbu), and bulky (ΔVal) ΔAAs exerting similar effects. The proteolytic stabilities of 1 and its analogs were determined by incubation with Pronase. Z-ΔAbu and ΔVal increased the resistance of peptides to proteolysis when incorporated at the 3-position and had negligible impact on stability when placed at the 1-position, whereas ΔAla-containing peptides degraded rapidly regardless of position. Exposure of peptides 2a–c and 3a–c to the reactive thiol cysteamine revealed that ΔAla-containing peptides underwent conjugate addition at room temperature, while Z-ΔAbu- and ΔVal-containing peptides were inert even at elevated temperatures. These results suggest that both bulky and the more synthetically accessible medium-sized ΔAAs should be valuable tools for bestowing rigidity and proteolytic stability on bioactive peptides.</div>

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Faculty Opinions recommendation of A proline-derived transannular N-cap for nucleation of short α-helical peptides.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726509368.793520986 ◽

2016 ◽

Author(s):

Paramjit Arora ◽

Michael Wuo

Keyword(s):

Helical Peptides

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How Do Channel- and Pore-Forming Helical Peptides Interact with Lipid Membranes and How does this Account for their Antimicrobial Activity?

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557023405963 ◽

2002 ◽

Vol 2 (4) ◽

pp. 331-342 ◽

Cited By ~ 10

Author(s):

Herve Duclohier

Keyword(s):

Antimicrobial Activity ◽

Lipid Membranes ◽

Helical Peptides

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Novel Scaffolds for Leishmania infantum Trypanothione Reductase Inhibitors Derived from Brazilian Natural Products Biodiversity

Anti-Infective Agents ◽

10.2174/2211352518666200131121308 ◽

2021 ◽

Vol 18 (4) ◽

pp. 398-418

Author(s):

Vinícius Guimarães da Paixão ◽

Samuel Silva da Rocha Pita

Keyword(s):

Natural Products ◽

Leishmania Infantum ◽

In Vitro Assays ◽

Current Therapy ◽

Pharmacokinetic Analysis ◽

Trypanothione Reductase ◽

Resistant Species ◽

Reductase Inhibitors ◽

Thiol Redox

Background: Leishmania infantum causes the most lethal form of Leishmaniasis: Visceral leishmaniasis. Current therapy for this disease is related to the development of drug-resistant species and toxicity. Trypanothione Reductase (LiTR), a validated target for the drug discovery process, is involved with parasites' thiol-redox metabolism. Objective: In this study, through Virtual Screening employing two distinct Natural Products Brazilian databases, we aimed to identify novel inhibitor scaffolds against LiTR. Results: Thus, the “top 10” LiTR-ligand energies have been selected and their interaction profiles into LiTR sites through the AuPosSOM server have been verified. Finally, Pred-hERG, Aggregator Advisor, FAF-DRUGS, pkCSM and DataWarrior were employed and their results allowed us to evaluate, respectively, the cardiotoxicity, aggregation capacity, presence of false-positive compounds (PAINS) and their toxicities. Conclusion: Three molecules that overcame the in silico pharmacokinetic analysis and have a good interaction with LiTR, were chosen to use in vitro assays hoping that our computational results reported here would aid the development of new anti-leishmanial compounds.

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