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  • Pharmacy  (24)
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  • 2020-2024  (24)
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  • Pharmacy  (24)
  • 1
    Online Resource
    Online Resource
    Conjugation of a Cationic Cell-Penetrating Peptide with a Novel Kunitzin-like Trypsin Inhibitor: New Insights for Enhancement of Peptide Bioactivities
    MDPI AG ; 2022
    In:  Pharmaceutics Vol. 14, No. 9 ( 2022-08-27), p. 1805-
    Details
    In: Pharmaceutics, MDPI AG, Vol. 14, No. 9 ( 2022-08-27), p. 1805-
    Abstract: Cationic cell-penetrating peptides (CPPs), such as transactivator of transcription (TAT) peptide, have been proposed as effective drug carriers to improve intracellular delivery of biological macromolecules. Amphibian skin-derived Kunitz-type trypsin inhibitors (KTIs), short counterparts of KTIs from plant sources, were found to possess potent serine protease inhibitory activity. However, poor transmembrane permeability of these molecules has largely hindered the study of the full spectrum of their biological actions. As a result, this study aimed to extend the biological activities of amphibian KTIs by their conjugation to cationic CPPs. Herein, a novel peptide (kunitzin-OV2) and its phenylalanine-substituted analogue F9-kunitzin-OV2 (F9-KOV2) were evaluated for inhibition of trypsin/chymotrypsin and showed weak antibacterial activity against Escherichia coli (E. coli). As expected, the conjugation to TAT peptide did not increase membrane lysis compared with the original kunitzin-OV2, but effectively assisted this complex to enter cells. TAT-kunitzin-OV2 (TAT-KOV2) exhibited a 32-fold increase in antibacterial activity and an enhanced bactericidal rate against E. coli. In addition, the conjugation enabled the parent peptides to exhibit antiproliferative activity against cancer cells. Interestingly, TAT-F9-kunitzin-OV2 (TAT-F9-KOV2) showed stronger antiproliferative activity against human breast cancer (MCF-7) and human glioblastoma (U251MG) cell lines, which TAT-KOV2 did not possess. Moreover, TAT-F9-KOV2 showed a 20–25-fold increase in antiproliferative capacity against human lung cancer (H157, H460) cell lines compared with TAT-KOV2. Therefore, the conjugation of CPPs effectively solves the problem of cell penetration that short KTIs lack and provides evidence for new potential applications for their subsequent development as new antibacterial and anticancer agents.
    Type of Medium: Online Resource
    ISSN: 1999-4923
    URL: Article
    DOI: 10.3390/pharmaceutics14091805
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2527217-2
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  • 2
    Online Resource
    Online Resource
    Structure–Activity Relationship and Molecular Docking of a Kunitz-Like Trypsin Inhibitor, Kunitzin-AH, from the Skin Secretion of Amolops hainanensis
    MDPI AG ; 2021
    In:  Pharmaceutics Vol. 13, No. 7 ( 2021-06-26), p. 966-
    Details
    In: Pharmaceutics, MDPI AG, Vol. 13, No. 7 ( 2021-06-26), p. 966-
    Abstract: Kunitz-like trypsin inhibitors are one of the most noteworthy research objects owing to their significance in pharmacological studies, including anticarcinogenic activity, obesity regulation and anticoagulation. In the current study, a novel Kunitz-like trypsin inhibitor, Kunitzin-AH, was isolated from the skin secretion of Amolops hainanensis. The novel peptide displayed a modest trypsin inhibitory activity with the inhibitor constant (Ki) value of 1.18 ± 0.08 µM without inducing damage to healthy horse erythrocytes. Then, a series of shortened variants of Kunitzin-AH were designed by truncating a peptide loop and site mutation inside the loop to illustrate the structure–activity relationship of the trypsin inhibition function. Among the variants, a significant decrease was observed for the Cys-Cys loop domain, while the extension of an Arg at N-terminus (RCKAAFC) retained the inhibitory activity, indicating that the -RCK-motif is essential in forming the reactive domain for exerting the inhibitory activity. Furthermore, substitutions of Ala by hydrophobic or hydrophilic residues decreased the activity, indicating suitable steric hindrance provides convenience for the combination of trypsin. Additionally, the conformational simulation of the analogues processed with Chimera and Gromacs and further combination simulations between the peptides and trypsin conducted with HDOCK offered a potential opportunity for the natural trypsin inhibitory drug design. The truncated sequence, AH-798, may be a good replacement for the full-length peptide, and can be optimized via cyclization for further study.
    Type of Medium: Online Resource
    ISSN: 1999-4923
    URL: Article
    DOI: 10.3390/pharmaceutics13070966
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2527217-2
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  • 3
    Online Resource
    Online Resource
    Brevinin-2GHk from Sylvirana guentheri and the Design of Truncated Analogs Exhibiting the Enhancement of Antimicrobial Activity
    MDPI AG ; 2020
    In:  Antibiotics Vol. 9, No. 2 ( 2020-02-14), p. 85-
    Details
    In: Antibiotics, MDPI AG, Vol. 9, No. 2 ( 2020-02-14), p. 85-
    Abstract: Brevinins are an important antimicrobial peptide (AMP) family discovered in the skin secretions of Ranidae frogs. The members demonstrate a typical C-terminal ranabox, as well as a diverse range of other structural characteristics. In this study, we identified a novel brevinin-2 peptide from the skin secretion of Sylvirana guentheri, via cloning transcripts, and identifying the expressed mature peptide, in the skin secretion. The confirmed amino acid sequence of the mature peptide was designated brevinin-2GHk (BR2GK). Moreover, as a previous study had demonstrated that the N-terminus of brevinin-2 is responsible for exerting antimicrobial activity, we also designed a series of truncated derivatives of BR2GK. The results show that the truncated derivatives exhibit significantly improved antimicrobial activity and cytotoxicity compared to the parent peptide, except a Pro14 substituted analog. The circular dichroism (CD) analysis of this analog revealed that it did not fold into a helical conformation in the presence of either lipopolysaccharides (LPS) or TFE, indicating that position 14 is involved in the formation of the α-helix. Furthermore, three more analogs with the substitutions of Ala, Lys and Arg at the position 14, respectively, revealed the influence on the membrane disruption potency on bacteria and mammalian cells by the structural changes at this position. Overall, the N-terminal 25-mer truncates demonstrated the potent antimicrobial activity with low cytotoxicity.
    Type of Medium: Online Resource
    ISSN: 2079-6382
    URL: Article
    DOI: 10.3390/antibiotics9020085
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2681345-2
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  • 4
    Online Resource
    Online Resource
    A Novel Strategy for the Design of Aurein 1.2 Analogs with Enhanced Bioactivities by Conjunction of Cell-Penetrating Regions
    MDPI AG ; 2023
    In:  Antibiotics Vol. 12, No. 2 ( 2023-02-19), p. 412-
    Details
    In: Antibiotics, MDPI AG, Vol. 12, No. 2 ( 2023-02-19), p. 412-
    Abstract: The rational design modification of membrane-active peptide structures by introducing additional membrane-penetrating regions has become a good strategy for the improvement of action and potency. Aurein 1.2 (GLFDIIKKIAESF-NH2) is a multifunctional antimicrobial peptide isolated from the green and golden bell frog, Litoria aurea, and the southern bell frog Litoria raniformis skin secretions. Its bio-functionality has been widely investigated. However, its lack of a potent action failed to provide aurein 1.2 with a competitive edge for further development as a therapeutic agent for clinical use. Herein, aurein 1.2 was chosen as a template for rational modification to achieve a more potent bio-functionality. KLA-2 (GLFDIIKKLAKLAESF-NH2), which a double KLA region inserted into the sequence, presented a 2–16-fold enhancement of antimicrobial activity, a 2–8-fold greater anti-biofilm activity (including biofilm prevention and eradication), and a 7-fold more potent anti-proliferation activity and hence was regarded as the most broad-spectrum active peptide. Additionally, with respect to antimicrobial activity, the IIKK-modified analog, IK-3 (GLFDIIKKIIKKIIKKI-NH2), also demonstrated a potent enhancement of activity against various pathogens, exhibiting a 2–8-fold enhanced activity compared to the parent peptide. Moreover, the selectivities of KLA-1 and KLA-2 were enhanced significantly. In conclusion, peptide modification, through the introduction of additional membrane penetrating regions, can increase both the potency and activity spectra of natural template peptides, making them suitable candidates for new drug development.
    Type of Medium: Online Resource
    ISSN: 2079-6382
    URL: Article
    DOI: 10.3390/antibiotics12020412
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2681345-2
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  • 5
    Online Resource
    Online Resource
    Broad-Spectrum Antimicrobial Activity and Improved Stability of a D-Amino Acid Enantiomer of DMPC-10A, the Designed Derivative of Dermaseptin Truncates
    MDPI AG ; 2020
    In:  Antibiotics Vol. 9, No. 9 ( 2020-09-21), p. 627-
    Details
    In: Antibiotics, MDPI AG, Vol. 9, No. 9 ( 2020-09-21), p. 627-
    Abstract: DMPC-10A (ALWKKLLKK-Cha-NH2) is a 10-mer peptide derivative from the N-terminal domain of Dermaseptin-PC which has shown broad-spectrum antimicrobial activity as well as a considerable hemolytic effect. In order to reduce hemolytic activity and improve stability to endogenous enzymes, a D-amino acid enantiomer (DMPC-10B) was designed by substituting all L-Lys and L-Leu with their respective D-form amino acid residues, while the Ala1 and Trp3 remained unchanged. The D-amino acid enantiomer exhibited similar antimicrobial potency to the parent peptide but exerted lower cytotoxicity and hemolytic activity. Meanwhile, DMPC-10B exhibited remarkable resistance to hydrolysis by trypsin and chymotrypsin. In addition to these advantages, DMPC-10B exhibited an outstanding antibacterial effect against Methicillin-resistant Staphylococcus aureus (MRSA) and Klebsiella pneumoniae using the Galleria mellonella larva model and displayed synergistic activities with gentamicin against carbapenem-resistant K. pneumoniae strains. This indicates that DMPC-10B would be a promising alternative for treating antibiotic-resistant pathogens.
    Type of Medium: Online Resource
    ISSN: 2079-6382
    URL: Article
    DOI: 10.3390/antibiotics9090627
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2681345-2
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  • 6
    Online Resource
    Online Resource
    Study on the Structure-Activity Relationship of an Antimicrobial Peptide, Brevinin-2GUb, from the Skin Secretion of Hylarana guentheri
    MDPI AG ; 2021
    In:  Antibiotics Vol. 10, No. 8 ( 2021-07-22), p. 895-
    Details
    In: Antibiotics, MDPI AG, Vol. 10, No. 8 ( 2021-07-22), p. 895-
    Abstract: Antimicrobial peptides (AMPs) are considered potential alternatives to antibiotics due to their advantages in solving antibiotic resistance. Brevinin-2GUb, which was extracted from the skin secretion of Hylarana guentheri, is a peptide with modest antimicrobial activity. Several analogues were designed to explore the structure–activity relationship and enhance its activity. In general, the Rana box is not an indispensable motif for the bioactivity of Brevinin-2GUb, and the first to the 19th amino acids at the N-terminal end are active fragments, such that shortening the peptide while maintaining its bioactivity is a promising strategy for the optimisation of peptides. Keeping a complete hydrophobic face and increasing the net charges are key factors for antimicrobial activity. With the increase of cationic charges, α-helical proportion, and amphipathicity, the activity of t-Brevinin-2GUb-6K (tB2U-6K), in combatting bacteria, drastically improved, especially against Gram-negative bacteria, and the peptide attained the capacity to kill clinical isolates and fungi as well, which made it possible to address some aspects of antibiotic resistance. Thus, peptide tB2U-6K, with potent antimicrobial activity against antibiotic-resistant bacteria, the capacity to inhibit the growth of biofilm, and low toxicity against normal cells, is of value to be further developed into an antimicrobial agent.
    Type of Medium: Online Resource
    ISSN: 2079-6382
    URL: Article
    DOI: 10.3390/antibiotics10080895
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2681345-2
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  • 7
    Online Resource
    Online Resource
    Progressive Design of a Ranatuerin-2 Peptide from Amolops wuyiensis: Enhancement of Bioactivity and In Vivo Efficacy
    MDPI AG ; 2023
    In:  Antibiotics Vol. 13, No. 1 ( 2023-12-19), p. 5-
    Details
    In: Antibiotics, MDPI AG, Vol. 13, No. 1 ( 2023-12-19), p. 5-
    Abstract: Antimicrobial peptides (AMPs) that exert multiple functions are considered promising candidates to combat the bacterial drug resistance crisis. Nowadays, targeted peptide modification has been widely recognised to improve biological activity and make up for deficiencies in clinical applications such as toxicity. In this study, a helix-loop peptide was isolated and identified from the skin secretion of the Wuyi torrent frog Amolops wuyiensis, namely, ranatuerin-2-AW (R2AW) (GFMDTAKNVAKNVAATLLDKLKCKITGGC). Target modifications were made to R2AW to study the structure–activity relationships and to optimise its bioactivities. Five analogues were progressively designed via residue substitution and truncation and the antibacterial and anticancer activities were evaluated. We found that the serine-substitution and cyclic-domain-deletion products showed similar antibacterial activity to the natural peptide R2AW, implying that the disulphide bridge and Rana box were dispensable for the antibacterial activity of ranatuerin-2 peptides. Notably, the cationicity- and hydrophobicity-enhanced variant, [Lys4,19, Leu20]R2AW(1-22)-NH2, exhibited significantly optimised antibacterial and anticancer activities. Additionally, it killed bacteria by membrane disruption at a highly efficient rate. Moreover, [Lys4,19, Leu20] R2AW(1-22)-NH2 exerted potential in vivo efficacy in a methicillin-resistant Staphylococcus aureus (MRSA)-infected waxworm model. Overall, this study demonstrated some rational design ideas for optimising the dual antibacterial and anticancer activities of ranatuerin-2 peptides and it proposes [Lys4,19, Leu20]R2AW(1-22)-NH2 as an appealing candidate for therapeutic development.
    Type of Medium: Online Resource
    ISSN: 2079-6382
    URL: Article
    DOI: 10.3390/antibiotics13010005
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2681345-2
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  • 8
    Online Resource
    Online Resource
    Kassporin-KS1: A Novel Pentadecapeptide from the Skin Secretion of Kassina senegalensis: Studies on the Structure-Activity Relationships of Site-Specific “Glycine-Lysine” Motif Insertions
    MDPI AG ; 2022
    In:  Antibiotics Vol. 11, No. 2 ( 2022-02-13), p. 243-
    Details
    In: Antibiotics, MDPI AG, Vol. 11, No. 2 ( 2022-02-13), p. 243-
    Abstract: Due to the abuse of traditional antibiotics and the continuous mutation of microbial resistance genes, microbial infections have become serious problems for human health. Therefore, novel antibacterial agents are urgently required, and amphibian antimicrobial peptides (AMP) are among the most interesting potential antibacterial leads. In this research, a novel peptide, named kassporin-KS1 (generically QUB-1641), with moderate antibacterial activity against Gram-positive bacteria, was discovered in the skin secretion of the Senegal running frog, Kassina senegalensis. Using site-specific sequence enrichment with a motif “glycine-lysine” that frequently occurs in ranid frog temporin peptides, a series of QUB-1641 analogues were synthesized, and effects on selected bioactivities were studied. The greatest activity enhancement was obtained when the “glycine-lysine” motif was located at the eighth and ninth position as in QUB-1570.QUB-1570 had a broader antibacterial spectrum than QUB-1641, and was eight-fold more potent. Moreover, QUB-1570 inhibited S. aureus biofilm most effectively, and significantly enhanced the viability of insect larvae infected with S. aureus. When the “glycine-lysine” motif of QUB-1570 was substituted to reduce the helix ratio and positive charge, the antibacterial activities of these synthetic analogues decreased. These data revealed that the “glycine-lysine” motif at positions 8 and 9 had the greatest enhancing effect on the antibacterial properties of QUB-1570 through increasing positive charge and helix content. This research may provide strategies for the site’s selective amino acid modification of some natural peptides to achieve the desired enhancement of activity.
    Type of Medium: Online Resource
    ISSN: 2079-6382
    URL: Article
    DOI: 10.3390/antibiotics11020243
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2681345-2
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  • 9
    Online Resource
    Online Resource
    Exenatide improves hypogonadism and attenuates inflammation in diabetic mice by modulating gut microbiota
    Elsevier BV ; 2023
    In:  International Immunopharmacology Vol. 120 ( 2023-07), p. 110339-
    Details
    In: International Immunopharmacology, Elsevier BV, Vol. 120 ( 2023-07), p. 110339-
    Type of Medium: Online Resource
    ISSN: 1567-5769
    URL: Article
    DOI: 10.1016/j.intimp.2023.110339
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 2043785-7
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  • 10
    Online Resource
    Online Resource
    Targeted Modification and Structure-Activity Study of GL-29, an Analogue of the Antimicrobial Peptide Palustrin-2ISb
    MDPI AG ; 2022
    In:  Antibiotics Vol. 11, No. 8 ( 2022-08-03), p. 1048-
    Details
    In: Antibiotics, MDPI AG, Vol. 11, No. 8 ( 2022-08-03), p. 1048-
    Abstract: Antimicrobial peptides (AMPs) are considered as promising antimicrobial agents due to their potent bioactivity. Palustrin-2 peptides were previously found to exhibit broad-spectrum antimicrobial activity with low haemolytic activity. Therefore, GL-29 was used as a template for further modification and study. Firstly, the truncated analogue, GL-22, was designed to examine the function of the ‘Rana box’, which was confirmed to have no impact on antimicrobial activity. The results of antimicrobial activity assessment against seven microorganisms demonstrated GL-22 to have a broad-spectrum antimicrobial activity, but weak potency against Candida albicans (C. albicans). These data were similar to those of GL-29, but GL-22 showed much lower haemolysis and lower cytotoxicity against HaCaT cells. Moreover, GL-22 exhibited potent in vivo activity at 4 × MIC against Staphylococcus aureus (S. aureus)-infected larvae. Several short analogues, from the C-terminus and N-terminus of GL-22, were modified to identify the shortest functional motif. However, the results demonstrated that the shorter peptides did not exhibit potent antimicrobial activity, and the factors that affect the bioactive potency of these short analogues need to be further studied.
    Type of Medium: Online Resource
    ISSN: 2079-6382
    URL: Article
    DOI: 10.3390/antibiotics11081048
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2681345-2
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