Towards designing globular antimicrobial peptide mimics: role of polar functional groups in biomimetic ternary antimicrobial polymers

Rani, Garima; Kuroda, Kenichi; Vemparala, Satyavani

doi:10.1039/d0sm01896a

Cited by 17 publications

(33 citation statements)

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“…Simulations of synthetic antimicrobial polymers performed in the presence of a representative lipid bilayer have increased understanding of the conformational changes to polymer chain that occur during the interaction with the bacterial membrane. [ 23n,79d,98,133 ] More recently, they have enabled the stabilization of proteins by random copolymers mediated by interactions between functionalities statistically distributed along the polymer chain and the corresponding spatially distributed patches on the protein surface. [ 42a,134 ]…”

Section: Discussionmentioning

confidence: 99%

“…[97d] Besides improving biocompatibility, a very recent molecular dynamics simulation study by Rani et al suggested that ternary random copolymers (as exemplified via a polymethacrylate system) adopt a more folded conformation and can penetrate deeper into bacteria membranes even though the ternary copoly mers lack the amphiphilic conformations typically found in binary copolymers that contain only cationic and hydrophobic moieties. [98] This is an interesting finding and may seem counterintuitive at first considering that a hydrophilic functionality would allow the polymer to penetrate better across the hydrophobic tails of a bacteria membrane. Taken together, these studies strengthen the case for including polar uncharged groups in the design of antimicrobial polymers-bearing in mind that most natural AMPs are also made up of polar uncharged serine and glycine amino acids.…”

Section: Incorporation Of Neutral Polar Groupsmentioning

confidence: 99%

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Bioactive Synthetic Polymers

et al. 2021

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Progress in these arenas has been driven by the discovery of inert, biocompatible polymers to provide the desired function without eliciting undesirable responses from the host environment. While concerns regarding the fate of these materials have led to an ongoing hunt for bioresorbable materials, it is important to note that synthetic polymers have been reported to elicit a biological response on their own. [2j,5] While the biological response is often toxic in nature and therefore undesirable for many applications, it poses a question: can the intrinsic bioactivity of synthetic polymers be harnessed for therapeutic interventions? This idea of intrinsic bioactivity is distinct from the long history of work pertaining to the use of synthetic polymers within biomedical settings. Polymers have indeed been extensively explored and continue to be investigated as (nano)carriers facilitating the delivery of bioactive payloads; in the majority of cases, the (nano)carrier bereft of its cargo is presented to provide little to no effect, demonstrating its role as an ideal delivery vehicle. [6] Polymers with intrinsic bioactivity diverge from this well-known concept by inducing biological change (i.e., bioactivity) by themselves in the absence of any conjugated or encapsulated species. [7] Interestingly, this previously posed question generated significant interest prior to the advent of drug-delivery approaches. [8] Among these early studies, a synthetic polymer, designated DIVEMA, garnered significant attention for its presentation of an outstanding breadth of bioactivity. [9] DIVEMA is a copolymer of divinyl ether (DVE) and maleic anhydride (MA) in a 1:2 ratio, with its proposed cyclopolymerization mechanism affording an in-chain pyran which consequently caused it to be more prominently known as Pyran copolymer. A hydrolyzed and neutralized version received the designation NSC 46015 and was approved for experimental clinical evaluation due to its antitumor activity against several cancers, including Adenocarcinoma 755, Lewis lung carcinoma, and Dunning ascites leukemia. [10] Moreover, its ability to induce interferon expression led to its evaluation against several viruses and reports of prophylactic action in murine models. DIVEMA has also demon strated antimicrobial activity against both Grampositive and Gram-negative bacteria and fungi. Despite this wide-ranging bioactivity, DIVEMA also presented a number of toxic side effects, the summation of which was not favorable for clinical use. Such side effects were common to many of the investigated synthetic polymers of the time and their failure in clinical trials is reflected in an absence of such therapeutic interventions as approved medicines.Synthetic polymers are omnipresent in society as textiles and packaging materials, in construction and medicine, among many other important applications. Alternatively, natural polymers play a crucial role in sustaining life and allowing organisms to adapt to their environments by performing key biological functions such as m...

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Section: Discussionmentioning

confidence: 99%

Section: Incorporation Of Neutral Polar Groupsmentioning

confidence: 99%

Bioactive Synthetic Polymers

et al. 2021

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“…The conformation of SS-free HAV-2B peptide is such that it acquires a strong facially amphipihilic character upon segregation of hydrophobic and hydrophilic residues. Different membrane-active agents including antimicrobial peptides (Leontiadou et al 2006 ; Mondal et al 2010 ; Vanni et al 2014 ), polymers (Baul et al 2014 ; Baul & Vemparala, 2015 , 2017 ; Palermo et al 2012 , 2013 ; Rahman et al 2018 ; Rani et al 2021 ) and other membrane-active molecules (Devanand et al 2019 ; Polley & Vemparala, 2013 ; Vemparala et al 2006 ) are known to acquire such amphipihilic conformations upon partitioning into cellular membranes. However, in SS11-47 (Fig.…”

Section: Discussionmentioning

confidence: 99%

Role of Disulphide Bonds in Membrane Partitioning of a Viral Peptide

2022

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The importance of disulphide bond in mediating viral peptide entry into host cells is well known. In the present work, we elucidate the role of disulphide (SS) bond in partitioning mechanism of membrane-active Hepatitis A Virus-2B (HAV-2B) peptide, which harbours three cysteine residues promoting formation of multiple SS-bonded states. The inclusion of SS-bond not only results in a compact conformation but also induces distorted α-helical hairpin geometry in comparison to SS-free state. Owing to these, the hydrophobic residues get buried, restricting the insertion of SS-bonded HAV-2B peptide into lipid packing defects and thus the partitioning of the peptide is completely or partly abolished. In this way, the disulphide bond can potentially regulate the partitioning of HAV-2B peptide such that the membrane remodelling effects of this viral peptide are significantly reduced. The current findings may have potential implications in drug designing, targeting the HAV-2B protein by promoting disulphide bond formation within its membrane-active region. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s00232-022-00218-0

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“…The conformation of SS-free HAV-2B peptide is such that it acquires a strong facially amphipihilic character upon segregation of hydrophobic and hydrophilic residues. Different membrane active agents including antimicrobial peptides [55,62,63], polymers [58,[64][65][66][67][68][69] and other membrane active molecules [70][71][72] are known to acquire such amphipihilic conformations upon partitioning into cellular membranes. However, in SS11-47 (Fig 6C ) and SS11-52 (Fig 6D ) states, the hydrophobic accessible surface area is limited resulting in mitigation of peptide partitioning.…”

Section: Discussionmentioning

confidence: 99%

Role of Disulfide Bonds in Membrane Partitioning of a Viral Peptide

Sikdar

Banerjee

Vemparala

2021

Preprint

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The importance of disulfide bond in mediating viral peptide entry into host cells is well known. In the present work, we elucidate the role of disulfide (SS) bond in partitioning mechanism of membrane active Hepatitis A Virus-2B (HAV-2B) peptide, which harbours three cysteine residues promoting formation of multiple SS-bonded states. The inclusion of SS-bond not only results in a compact conformation but also induces distorted α-helical hairpin geometry in comparison to SS-free state, resulting in reduced hydrophobic exposure. Owing to this, the partitioning of HAV-2B peptide is completely or partly abolished. In a way, the disulfide bond regulates the partitioning of HAV-2B peptide, such that the membrane remodelling effects of this viral peptide are significantly reduced. The current findings may have potential implications in drug designing, targeting the HAV-2B protein by promoting disulfide bond formation within its membrane active region.

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Towards designing globular antimicrobial peptide mimics: role of polar functional groups in biomimetic ternary antimicrobial polymers

Abstract: Using atomistic molecular dynamics simulations, we study the interaction of ternary methacrylate polymers, composed of charged cationic, hydrophobic and neutral polar groups, with model bacterial membrane.

Cited by 17 publications

References 72 publications

Bioactive Synthetic Polymers

Bioactive Synthetic Polymers

Role of Disulphide Bonds in Membrane Partitioning of a Viral Peptide

Role of Disulfide Bonds in Membrane Partitioning of a Viral Peptide

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