Topological effects on the designability and bactericidal potency of antimicrobial peptides

Hazam, Prakash Kishore; Akhil, R.; Jerath, Gaurav; Saikia, Jahnu; Ramakrishnan, Vibin

doi:10.1016/j.bpc.2019.02.005

Cited by 28 publications

(13 citation statements)

References 40 publications

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“…Although there are many heterogeneous amino acid sequences and variations of the secondary structure of the peptides that have been introduced, they are generally cationic, amphipathic, and mainly carry on an α-helix structure. These characteristics will facilitate the peptides to interact with and disrupt the lipid of cell membranes [ 15 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Novel Antimicrobial Peptides from a Cecropin-Like Region of Heteroscorpine-1 from Heterometrus laoticus Venom with Membrane Disruption Activity

et al. 2021

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The increasing antimicrobial-resistant prevalence has become a severe health problem. It has led to the invention of a new antimicrobial agent such as antimicrobial peptides. Heteroscorpine-1 is an antimicrobial peptide that has the ability to kill many bacterial strains. It consists of 76 amino acid residues with a cecropin-like region in N-terminal and a defensin-like region in the C-terminal. The cecropin-like region from heteroscorpine-1 (CeHS-1) is similar to cecropin B, but it lost its glycine-proline hinge region. The bioinformatics prediction was used to help the designing of mutant peptides. The addition of glycine-proline hinge and positively charged amino acids, the deletion of negatively charged amino acids, and the optimization of the hydrophobicity of the peptide resulted in two mutant peptides, namely, CeHS-1 GP and CeHS-1 GPK. The new mutant peptide showed higher antimicrobial activity than the native peptide without increasing toxicity. The interaction of the peptides with the membrane showed that the peptides were capable of disrupting both the inner and outer bacterial cell membrane. Furthermore, the SEM analysis showed that the peptides created the pore in the bacterial cell membrane resulted in cell membrane disruption. In conclusion, the mutants of CeHS-1 had the potential to develop as novel antimicrobial peptides.

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Section: Introductionmentioning

confidence: 99%

Novel Antimicrobial Peptides from a Cecropin-Like Region of Heteroscorpine-1 from Heterometrus laoticus Venom with Membrane Disruption Activity

et al. 2021

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“…The rearrangement of secondary structure results in the formation of a definite secondary amphipathicity profile and spatial charge distribution, unique to each peptide model, which can be envisaged as spatial fingerprints responsible for the permeation of the cell membrane. Though disordered peptides can also penetrate live cell membranes, the designability of such intrinsically disordered peptides as CPPs is limited . The uncertainty in adopting a specific fold further adds to the obstacles for designing CPPs with tailored functions .…”

Section: Introductionmentioning

confidence: 99%

“…Though disordered peptides can also penetrate live cell membranes, 12 the designability of such intrinsically disordered peptides as CPPs is limited. 13 The uncertainty in adopting a specific fold further adds to the obstacles for designing CPPs with tailored functions. 14,15 To design peptides with tailored functions, it is vital to confine the peptide backbone architecture to a defined conformation; else, we have to wait for random hits with very minimal possibility of an informed and structured design paradigm getting established.…”

Section: Introductionmentioning

confidence: 99%

Conformationally constrained peptides for drug delivery

Jerath

Goyal

Trivedi

et al. 2020

Journal of Peptide Science

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Peptides have shown great potential in acting as template for developing versatile carrier platforms in nanomedicine, aimed at selective delivery of drugs to only pathological tissues saving its normal neighbors. Cell‐penetrating peptides (CPPs) are short oligomeric peptides capable of translocating across the cell membrane while simultaneously employing multiple mechanisms of entry. Most CPPs exist as disordered structures in solution and may adopt a helical conformation on interaction with cell membrane, vital to their penetrative capability. Herein, we report a series of cationic helical amphipathic peptides (CHAPs), which are topologically constrained to be helical. The peptides were tested against cervical and breast cancer cells for their cell penetration and drug delivery potential. The cellular uptake of CHAP peptides is independent of temperature and energy availability. The activity of the peptides is biocompatible in bovine serum. CHAPs delivered functional methotrexate (MTX) inside the cell as CHAP‐MTX conjugates. CHAP‐MTX conjugates were more toxic to cancer cells than MTX alone. However, the CHAP‐MTX conjugates were less toxic to HEK‐293 cells compared with the cancer cells suggesting higher affinity towards cancer cells.

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“…It is reported that palmitoylated bovine-β-defensin-2 (BNBD-2) interact more efficiently with membrane in presence of NaCl, thus improving the antibacterial activity [22]. In a recent study [23], demonstrated that peptide chain length and conformation locking are very critical parameters while designing potent novel antimicrobial peptide.…”

Section: Introductionmentioning

confidence: 99%

Analysis of mutations of defensin protein using accelerated molecular dynamics simulations

et al. 2020

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Plant defensins possess diverse biological functions that include antifungal and antibacterial activities and α-amylase and trypsin inhibitory properties. Two mutations, G9R and V39R, were confirmed to increase the antifungal activity of Raphanus sativus antifungal protein 2 (RsAFP2). Accelerated Molecular Dynamics (aMD) were carried out to examine the conformational changes present in these RsAFP2 mutants, and its two closest homologs compared to the wild-type protein. Specifically, the root mean square fluctuation values for the eight cysteine amino acids involved in the four disulfide bonds were low in the V39R mutant compared to the wild-type. Additionally, analysis of the free energy change revealed that G9R and V39R mutations exert a neutral and stabilizing effect on RsAFP2 conformation, and this is supported by the observed lower total energy of mutants compared to the wild-type, suggesting that enhanced stability of the mutants. However, MD simulations to a longer time scale would aid in capturing more conformational state of the wild-type and mutants defensin protein. Furthermore, the aMD simulations on fungal mimic membranes with RsAFP2 and its mutants and homologs showed that the mutant proteins caused higher deformation and water diffusion than the native RsAFP2, especially the V39R mutant. The mutant variants seem to interact by specifically targeting the POPC and POPI lipids amongst others. This work highlights the stabilizing effect of mutations at the 9th and 39th positions of RsAFP2 and their increased membrane deformation activity.

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Topological effects on the designability and bactericidal potency of antimicrobial peptides

Cited by 28 publications

References 40 publications

Novel Antimicrobial Peptides from a Cecropin-Like Region of Heteroscorpine-1 from Heterometrus laoticus Venom with Membrane Disruption Activity

Novel Antimicrobial Peptides from a Cecropin-Like Region of Heteroscorpine-1 from Heterometrus laoticus Venom with Membrane Disruption Activity

Conformationally constrained peptides for drug delivery

Analysis of mutations of defensin protein using accelerated molecular dynamics simulations

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