Probing the disparate effects of arginine and lysine residues on antimicrobial peptide/bilayer association

Rice, Amy; Wereszczynski, Jeff

doi:10.1016/j.bbamem.2017.06.002

Cited by 47 publications

(42 citation statements)

References 74 publications

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“…The work highlights that while the net charge of a carrier can help predict its electro-diffusive behavior, the type of amino acid moiety in the peptide [43, 47, 48] and its spatial distribution [33, 49–51] are also important to consider. The change in uptake of arginine rich CPCs between 50% and 90% GAG depletion, was less significant than the change from healthy to 50% GAG depleted cartilage.…”

Section: Discussionmentioning

confidence: 99%

Cartilage penetrating cationic peptide carriers for applications in drug delivery to avascular negatively charged tissues

et al. 2019

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Drug delivery to avascular, negatively charged tissues like cartilage remains a challenge. The constant turnover of synovial fluid results in short residence time of administered drugs in the joint space and the dense negatively charged matrix of cartilage hinders their diffusive transport. Drugs are, therefore, unable to reach their cell and matrix targets in sufficient doses, and fail to elicit relevant biological response, which has led to unsuccessful clinical trials. The high negative fixed charge density (FCD) of cartilage, however, can be used to convert cartilage from a barrier to drug entry into a depot by making drugs positively charged. Here we design cartilage penetrating and binding cationic peptide carriers (CPCs) with varying net charge, spatial distribution and hydrophobicity to deliver large-sized therapeutics and investigate their electro-diffusive transport in healthy and arthritic cartilage. We showed that CPC uptake increased with increasing net charge up to +14 but dropped as charge increased further due to stronger binding interactions that hindered CPC penetrability and uptake showing that weak-reversible binding is key to enable their penetration through full tissue thickness. Even after 90% GAG depletion, while CPC +14 uptake reduced by over 50% but still had a significantly high value of 148x showing that intra-tissue long-range charge-based binding is further stabilized by short-range H-bond and hydrophobic interactions. The work presents an approach for rational design of cationic carriers based on tissue FCD and properties of macromolecules to be delivered. These design rules can be extended to drug delivery for other avascular, negatively charged tissues.

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Section: Discussionmentioning

confidence: 99%

Cartilage penetrating cationic peptide carriers for applications in drug delivery to avascular negatively charged tissues

et al. 2019

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“…The zwitterionic properties of arginine and butyroyl arginine likely enhance viral inactivation through strong lipid binding and self‐interactions. Alone, guanidinium is able to form multiple hydrogen bonds with lipids . However, in combination with the strong charge distribution of arginine, the hydrogen binding of guanidinium to lipids is strengthened .…”

Section: Virus Inactivation With Argininementioning

confidence: 99%

“…In support of Hypothesis 2, arginine does interact with the lipid bilayer through binding and lipid deformations. Specifically, arginine‐rich peptides deform membranes in order to translocate into the cell for drug delivery . At low arginine concentrations, endocytosis has been observed as the sole route for arginine peptide translocation .…”

Section: Hypotheses For Synergistic Arginine Viral Inactivationmentioning

confidence: 99%

“…Although arginine peptides do have a different charge/size ratio in comparison to a single arginine molecule, the guanidinium group on arginine is a large component of peptide activity . Membrane deformations result from the guanidinium moiety binding to negative charges on the lipid bilayer, and/or the hydrophilic peptides interacting with the hydrophobic lipids . Arginine side chains also maintain their charge when exposed to the hydrophobic membrane environment where no other amino acid can, aiding further in membrane deformations .…”

Section: Hypotheses For Synergistic Arginine Viral Inactivationmentioning

confidence: 99%

“…In several studies, arginine‐rich peptides have been shown to cross the lipid bilayer through the formation of a water pore . Pores are hypothesized to form in a similar manner to membrane deformations, through electrostatic or hydrophilic interactions . For example, preferential binding to negative charges in zwitterionic lipids (common in mammalian membranes) results in lipid sorting and membrane tension.…”

Section: Hypotheses For Synergistic Arginine Viral Inactivationmentioning

confidence: 99%

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Arginine‐enveloped virus inactivation and potential mechanisms

Meingast

Heldt

2019

Biotechnology Progress

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Arginine synergistically inactivates enveloped viruses at a pH or temperature that does little harm to proteins, making it a desired process for therapeutic protein manufacturing. However, the mechanisms and optimal conditions for inactivation are not fully understood, and therefore, arginine viral inactivation is not used industrially. Optimal solution conditions for arginine viral inactivation found in the literature are high arginine concentrations (0.7–1 M), a time of 60 min, and a synergistic factor of high temperature (≥40°C), low pH (≤pH 4), or Tris buffer (5 mM). However, at optimal conditions full inactivation does not occur over all enveloped viruses. Enveloped viruses that are resistant to arginine often have increased protein stability or membrane stabilizing matrix proteins. Since arginine can interact with both proteins and lipids, interaction with either entity may be key to understanding the inactivation mechanism. Here, we propose three hypotheses for the mechanisms of arginine induced inactivation. Hypothesis 1 describes arginine‐induced viral inactivation through inhibition of vital protein function. Hypothesis 2 describes how arginine destabilizes the viral membrane. Hypothesis 3 describes arginine forming pores in the virus membrane, accompanied by further viral damage from the synergistic factor. Once the mechanisms of arginine viral inactivation are understood, further enhancement by the addition of functional groups, charges, or additives may allow the inactivation of all enveloped viruses in mild conditions.

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Conjugation of Polycationic Peptides Extends the Efficacy Spectrum of β‐Lactam Antibiotics

Werner,

Umstätter,

Böhmann

et al. 2024

Advanced Science

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Antibiotic‐resistant enterococci represent a significant global health challenge. Unfortunately, most β‐lactam antibiotics are not applicable for enterococcal infections due to intrinsic resistance. To extend their antimicrobial spectrum, polycationic peptides are conjugated to examples from each of the four classes of β‐lactam antibiotics. Remarkably, the β‐lactam–peptide conjugates gained an up to 1000‐fold increase in antimicrobial activity against vancomycin‐susceptible and vancomycin‐resistant enterococci. Even against β‐lactam‐resistant Gram‐negative strains, the conjugates are found to be effective despite their size exceeding the exclusion volume of porins. The extraordinary gain of activity can be explained by an altered mode of killing. Of note, the conjugates showed a concentration‐dependent activity in contrast to the parent β‐lactam antibiotics that exhibited a time‐dependent mode of action. In comparison to the parent β‐lactams, the conjugates showed altered affinities to the penicillin‐binding proteins. Furthermore, it is found that peptide conjugation also resulted in a different elimination route of the compounds when administered to rodents. In mice systemically infected with vancomycin‐resistant enterococci, treatment with a β‐lactam–peptide conjugate reduced bacterial burden in the liver compared to its originator. Therefore, peptide modification of β–lactam antibiotics represents a promising platform strategy to broaden their efficacy spectrum, particularly against enterococci.

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Probing the disparate effects of arginine and lysine residues on antimicrobial peptide/bilayer association

Cited by 47 publications

References 74 publications

Cartilage penetrating cationic peptide carriers for applications in drug delivery to avascular negatively charged tissues

Cartilage penetrating cationic peptide carriers for applications in drug delivery to avascular negatively charged tissues

Arginine‐enveloped virus inactivation and potential mechanisms

Conjugation of Polycationic Peptides Extends the Efficacy Spectrum of β‐Lactam Antibiotics

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