Spermine-Conjugated Short Proline-Rich Lipopeptides as Broad-Spectrum Intracellular Targeting Antibacterial Agents

Dewangan, Rikeshwer Prasad; Verma, Devesh Pratap; Verma, Neeraj Kumar; Gupta, Ankit; Pant, Garima; Mitra, Kalyan; Habib, Saman; Ghosh, Jimut Kanti

doi:10.1021/acs.jmedchem.1c01809

Cited by 19 publications

(7 citation statements)

References 63 publications

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“…Polyamines are important structural components used in a variety of applications. 23 We believe that the method developed in this study will be useful for supplying structurally defined, diverse, and homogeneous polyamines for a variety of biochemical studies.…”

Section: Discussionmentioning

confidence: 98%

Synthesis of a fully protected long-chain polyamine subunit of aculeine B using the photoremovable NPEC group

et al. 2023

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Section: Discussionmentioning

confidence: 98%

Synthesis of a fully protected long-chain polyamine subunit of aculeine B using the photoremovable NPEC group

et al. 2023

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“…Supramolecular macrocyclic peptides are an appealing platform for the construction of modern bio-materials with remarkable antibacterial activity, as novel antibiotics to combat bacterial resistance ( Gao et al, 2021 ). Glycopeptides, as promising broad-spectrum antimicrobial agents, are worth mentioning too ( Dewangan et al, 2021 ; Acharya et al, 2022 ).…”

Section: Landscape Of Opportunities: Topical Insightsmentioning

confidence: 99%

Smart therapies against global pandemics: A potential of short peptides

et al. 2022

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BackgroundAs we entered the third year of this pandemic, since the World Health Organisation (WHO) declared in March 2020 the novel coronavirus severe acute respiratory syndrome (SARS-CoV2) outbreak as a global pandemic COVID-19 (COronaVIrus Disease 19), we are still fighting with newer and newer viral mutations. The pandemic has passed the grim milestone of over 6.4 million COVID19 deaths, from more than 550 million reported cases thus far. In fact, more than 15 million people can die by the end of this year. It is highly likely that this pandemic will become endemic, while the full evolutionary potential of coronaviruses has yet to be revealed. The next pandemic is coming. A microbe with features of SARS-Middle East respiratory syndrome (MERS) and SARS-CoV-2 could lead to significantly more catastrophic loss of life. The co-evolution with other viruses should not be neglected. According to the WHO, we should expect diverse zoonotic, outbreakprone microbes, including highly pathogenic strains of influenza, Nipah, Ebola, Zika, or hemorrhagic fever viruses. 'It's an evolutionary certainty that there will be another virus with the potential to be more transmittable and deadly than this one', said Tedros Adhanom Ghebreyesus, director-general of the WHO. On the other hand, in both poor countries and regions of armed conflict, where vaccination is hampered, historic diseases are re-emerging, with migration and displacement influencing transmission risk and limiting control, and raising potential for additional outbreaks. Furthermore, there are other looming terrible threats to humanity as damaging as the bubonic plagues, such as bioterrorism or antibiotic resistant microorganisms. In most cases, both effective prevention and treatment options are limited.

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“…Membrane disruptive antimicrobial peptides (AMPs), which occur naturally as part of the innate immune system, offer an opportunity to address multidrug-resistant (MDR) bacteria because of their unspecific mechanism of action, against which resistance does not occur easily. − Such AMPs are however unstable in serum and most often toxic owing to their membrane disruptive amphiphilic and usually α-helical structure triggering their antibacterial effect. Their properties can be improved by sequence optimization, − whereby the most versatile approach consists in introducing non-natural structural elements such as d -amino acids, − non-natural residues, β- or γ-amino acids, , isopeptide bonds, or entirely non-peptidic elements such as spermine or fatty acids. , A complete redesign of AMPs is also possible in the form of dimers, cyclic or bicyclic staples, − small molecules, peptoids, , foldamers, or dendrimers. , …”

Section: Introductionmentioning

confidence: 99%

To Fold or Not to Fold: Diastereomeric Optimization of an α-Helical Antimicrobial Peptide

Personne,

Paschoud,

Fulgencio

et al. 2023

J. Med. Chem.

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Membrane disruptive α-helical antimicrobial peptides (AMPs) offer an opportunity to address multidrug resistance; however, most AMPs are toxic and unstable in serum. These limitations can be partly overcome by introducing D-residues, which often confers protease resistance and reduces toxicity without affecting antibacterial activity, presumably due to lowered α-helicity. Here, we investigated 31 diastereomers of the α-helical AMP KKLLKLLKLLL. Three diastereomers containing two, three, and four D-residues showed increased antibacterial effects, comparable hemolysis, reduced toxicity against HEK293 cells, and excellent serum stability, while another diastereomer with four D-residues additionally displayed lower hemolysis. X-ray crystallography confirmed that high or low α-helicity as measured by circular dichroism indicated α-helical or disordered structures independently of the number of chirality switched residues. In contrast to previous reports, α-helicity across diastereomers correlated with both antibacterial activity and hemolysis and revealed a complex relationship between stereochemistry, activity, and toxicity, highlighting the potential of diastereomers for property optimization.

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Spermine-Conjugated Short Proline-Rich Lipopeptides as Broad-Spectrum Intracellular Targeting Antibacterial Agents

Cited by 19 publications

References 63 publications

Synthesis of a fully protected long-chain polyamine subunit of aculeine B using the photoremovable NPEC group

Synthesis of a fully protected long-chain polyamine subunit of aculeine B using the photoremovable NPEC group

Smart therapies against global pandemics: A potential of short peptides

To Fold or Not to Fold: Diastereomeric Optimization of an α-Helical Antimicrobial Peptide

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