Synergistic antiviral activity against drug-resistant HIV-1 by naturally occurring dipeptide and A single-stranded oligonucleotide

Ceña-Díez, Rafael; Spetz, Anna-Lena; Sönnerborg, Anders

doi:10.1016/j.drup.2023.100955

Cited by 3 publications

(3 citation statements)

References 10 publications

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“…Nevertheless, substituting these bonds with carbocycles produces biologically active peptides, but their activity decreases by tenfold. These findings contradict the ease of isolating antiviral peptidyl metabolites like tripeptides (Hu et al, 2021), dipeptides (Ceña-Diez et al, 2023), and 2-5-diketopiperazines (Huang et al, 2014).…”

Section: Significant Activity Of Mespefs Against Influenza a Virusmentioning

confidence: 86%

The high-throughput solid-phase extraction of cis-cyclo(L-Leu-L-Pro) and cis-cyclo(L-Phe-L-Pro) from Lactobacillus plantarum demonstrates efficacy against multidrug-resistant bacteria and influenza A (H3N2) virus

Son,

Hong,

Seong

et al. 2024

Front. Mol. Biosci.

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Introduction: 2,5-diketopiperazines are the simplest forms of cyclic dipeptides (CDPs) and have diverse frameworks with chiral side chains that are useful for drug development. Previous research has investigated the antimicrobial properties of proline-linked CDPs and their combinations in the culture filtrate (CF) of Lactobacillus plantarum LBP-K10 using anion exchange chromatography (AEC). However, the quantity of CDPs showcasing notable anti-influenza virus activity derived from AECs was generally lower than those originating from Lactobacillus CF.Methods: To address this issue, the study aims to propose a more efficient method for isolating CDPs and to introduce the antiviral combinations of CDPs obtained using a new method. The study employed a novel technique entailing high-throughput C18-based solid-phase extraction with a methanol gradient (MeSPE). The MeSPE method involved increasing the methanol concentration from 5% to 50% in 5% increments.Results: The methanol SPE fractions (MeSPEfs) eluted with methanol concentrations between 35% and 45% evinced substantial efficacy in inhibiting the influenza A/H3N2 virus via plaque-forming assay. MeSPEf-45, the 45% MeSPEf, exhibited exceptional efficacy in preventing viral infections in Madin-Darby kidney cells, surpassing both individual CDPs and the entire set of MeSPEfs. To identify the specific antiviral components of MeSPEf-45, all MeSPEfs were further fractionated through preparative high-performance liquid chromatography (prep-HPLC). MeSPEf-45 fractions S8 and S11 presented the highest activity against multidrug-resistant bacteria and influenza A/H3N2 virus among all MeSPEfs, with 11 common fractions. Antiviral fractions S8 and S11 were identified as proline-based CDPs, specifically cis-cyclo(L-Leu-L-Pro) and cis-cyclo(L-Phe-L-Pro), using gas chromatography-mass spectrometry. The combination of MeSPEf-45 fractions S8 and S11 displayed superior antibacterial and anti-influenza virus effects compared to the individual fractions S8 and S11.Discussion: High-throughput MeSPE-derived MeSPEfs and subsequent HPLC-fractionated fractions presents an innovative approach to selectively purify large amounts of potent antimicrobial CDPs from bacterial CF. The findings also show the effectiveness of physiologically bioactive combinations that utilize fractions not containing CDP. This study provides the initial evidence demonstrating the antimicrobial properties of CDPs acquired through high-throughput SPE techniques.

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Section: Significant Activity Of Mespefs Against Influenza a Virusmentioning

confidence: 86%

The high-throughput solid-phase extraction of cis-cyclo(L-Leu-L-Pro) and cis-cyclo(L-Phe-L-Pro) from Lactobacillus plantarum demonstrates efficacy against multidrug-resistant bacteria and influenza A (H3N2) virus

Son,

Hong,

Seong

et al. 2024

Front. Mol. Biosci.

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“…Despite this anticipation, our findings demonstrated a notable synergistic relationship between WG-am and these compounds. Previously, we showed a synergy of WG-am and TDF against NRTI-resistant isolates 7324–1 and 52534–2 using the CalcuSyn software ( Cena-Diez et al., 2022 ; Cena-Diez et al., 2023b ). However, in the current manuscript, we expanded this finding and now report a synergy extended to all isolates exhibiting resistance against NNRTIs and NRTIs.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, we described the low toxicity and synergistic profile of WG-am and another novel antiviral compound, ssON, against drug-resistant HIV-1 ( Cena-Diez et al., 2022 ; Cena-Diez et al., 2023b ). To further study the efficacy of WG-am in combination with approved antiretrovirals, we now investigated its anti-HIV-1 activity combined with four antiretroviral agents from four classes: the protease inhibitor (PI) darunavir (DRV), the INSTI raltegravir (RAL), the nucleotide reverse transcriptase inhibitor (NRTI) tenofovir disoproxil fumarate (TDF), and the non-nucleoside RTI (NNRTI) efavirenz (EFV).…”

Section: Introductionmentioning

confidence: 99%

Broad synergistic antiviral efficacy between a novel elite controller-derived dipeptide and antiretrovirals against drug-resistant HIV-1

Giammarino,

Sönnerborg,

Ceña-Diez

2024

Front. Cell. Infect. Microbiol.

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IntroductionThe naturally occurring dipeptide Tryptophylglycine (WG) is enhanced in human immunodeficiency virus (HIV-1) infected Elite Controllers (EC). We have shown that this dipeptide has an anti-HIV-1 effect and evaluated now its synergistic antiretroviral activity, in combination with current antiretrovirals against multi-drug resistant HIV-1 isolates.MethodsDrug selectivity assay with WG-am and ARVs agains HIV-1 resistant isolates were carried out. Subsequently, two methods, Chou-Talalay’s Combination Index (CI) and ZIP synergy score (SS), were used to quantify the synergism.ResultsWG-am had a moderate/strong synergism with the four tested antiretrovirals: raltegravir, tenofovir, efavirenz, darunavir. WG-am:TDF had strong synergism at ED50, ED75, ED90 (CI: <0.2) in isolates resistant to protease inhibitors or integrase strand inhibitors (INSTI), and a slightly less synergism in isolates resistant to non-nucleoside or nucleotide reverse transcriptase inhibitors. WG-am combined with each of the four drugs inhibited all drug-resistant isolates with over 95% reduction at maximum concentration tested. The highest selectivity indexes (CC50/ED50) were in INSTI-resistant isolates.ConclusionOur data suggest that WG, identified as occurring and enhanced in Elite Controllers has a potential to become a future treatment option in patients with HIV-1 strains resistant to any of the four major categories of anti-HIV-1 compounds.

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Synergistic antiviral activity against drug-resistant HIV-1 by naturally occurring dipeptide and A single-stranded oligonucleotide

Cited by 3 publications

References 10 publications

The high-throughput solid-phase extraction of cis-cyclo(L-Leu-L-Pro) and cis-cyclo(L-Phe-L-Pro) from Lactobacillus plantarum demonstrates efficacy against multidrug-resistant bacteria and influenza A (H3N2) virus

The high-throughput solid-phase extraction of cis-cyclo(L-Leu-L-Pro) and cis-cyclo(L-Phe-L-Pro) from Lactobacillus plantarum demonstrates efficacy against multidrug-resistant bacteria and influenza A (H3N2) virus

Broad synergistic antiviral efficacy between a novel elite controller-derived dipeptide and antiretrovirals against drug-resistant HIV-1

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