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  1. Knotting terminal ends of mutant T1 lipase with disulfide bond improved structure rigidity and stability
    Hamdan SH, Maiangwa J, Nezhad NG, Ali MSM, Normi YM, Shariff FM, et al.
    Appl Microbiol Biotechnol, 2023 Mar;107(5-6):1673-1686.
    PMID: 36752811 DOI: 10.1007/s00253-023-12396-5
    Lipase biocatalysts offer unique properties which are often impaired by low thermal and methanol stability. In this study, the rational design was employed to engineer a disulfide bond in the protein structure of Geobacillus zalihae T1 lipase in order to improve its stability. The selection of targeted disulfide bond sites was based on analysis of protein spatial configuration and change of Gibbs free energy. Two mutation points (S2C and A384C) were generated to rigidify the N-terminal and C-terminal regions of T1 lipase. The results showed the mutant 2DC lipase improved methanol stability from 35 to 40% (v/v) after 30 min of pre-incubation. Enhancement in thermostability for the mutant 2DC lipase at 70 °C and 75 °C showed higher half-life at 70 °C and 75 °C for 30 min and 52 min, respectively. The mutant 2DC lipase maintained the same optimum temperature (70 °C) as T1 lipase, while thermally induced unfolding showed the mutant maintained higher rigidity. The kcat/Km values demonstrated a relatively small difference between the T1 lipase (WT) and 2DC lipase (mutant). The kcat/Km (s-1 mM-1) of the T1 and 2DC showed values of 13,043 ± 224 and 13,047 ± 312, respectively. X-ray diffraction of 2DC lipase crystal structure with a resolution of 2.04 Å revealed that the introduced single disulfide bond did not lower initial structural interactions within the residues. Enhanced methanol and thermal stability are suggested to be strongly related to the newly disulfide bridge formation and the enhanced compactness and rigidity of the mutant structure. KEY POINTS: • Protein engineering via rational design revealed relative improved enzymatic performance. • The presence of disulfide bond impacts on the rigidity and structural function of proteins. • X-ray crystallography reveals structural changes accompanying protein modification.
    Matched MeSH terms: Disulfides/chemistry
  2. Synthesis and Antitumor Evaluation of Glutathione Responsive Self-Immolative Disulphide Linked Camptothecin-Biotin Conjugate
    Kaur A, Dhiman S, Lee HB, Sharma M
    Anticancer Agents Med Chem, 2022;22(18):3182-3192.
    PMID: 35469577 DOI: 10.2174/1871520622666220425114553
    BACKGROUND: Camptothecin is a naturally occurring alkaloid obtained from the stem wood of the Chinese tree, Camptotheca acuminata. It exerts pharmacological effects due to its ability to selectively inhibit the type-I topoisomerase DNA nuclear enzyme. Several semisynthetic analogs of camptothecin have been synthesized to date possessing antitumor activity.

    OBJECTIVE: Camptothecin (CPT) is one of the most promising anticancer drugs but it produces various side effects because of its non-selectivity towards cancer cells. To overcome these adverse effects, we synthesized biotin conjugate of camptothecin, which was linked via a self-immolative disulfide linker (CPT-SS-Biotin).

    METHODS: Biotin conjugated camptothecin linked through a disulfide bond was synthesized following schemes, and the structural characterization was carried out. The stability and drug release studies were performed in the presence of glutathione (GSH) while in vitro studies were performed on 4T1 tumor cell lines. In vivo pharmacological investigation was done using an antitumor Wistar rat model.

    RESULTS: The stability and drug release studies were performed in the presence of glutathione (GSH), and CPT-SSBiotin was found to be physiologically stable moiety and can only be cleaved in the presence of GSH to release free CPT. The CPT-SS-Biotin showed higher toxicity in the biotin-overexpressing 4T1 tumor cell line with a lower IC50 value (8.44 μM) compared to camptothecin alone (IC50 > 30 μM). CPT-SS-Biotin also showed 10.6% higher cellular uptake by cells in comparison to free camptothecin. The CPT-SS-Biotin was delivered to cells by binding to the biotin receptors on the cell surface, followed by energy-dependent endocytosis and internalization to cause cellular toxicity.

    CONCLUSION: In-vivo tumor suppression studies and in vitro cell line studies along with serological parameters and histopathological studies showed that conjugate produced a high therapeutic effect and remarkably reduced toxic effects in comparison to free CPT. The results suggested that biotinylation of camptothecin via disulfide linker can be a safe and efficacious method in cancer therapeutics.

    Matched MeSH terms: Disulfides/chemistry
  3. Light exposure accelerates oxidative protein polymerization in beef stored in high oxygen atmosphere
    Zainudin MAM, Poojary MM, Jongberg S, Lund MN
    Food Chem, 2019 Nov 30;299:125132.
    PMID: 31299519 DOI: 10.1016/j.foodchem.2019.125132
    Protein oxidation of beef patties stored in high oxygen modified atmosphere packaging for 9 days was investigated. Meat was either stored in the dark, under light, or in the dark with addition of FeCl2/H2O2/myoglobin (forced oxidation). SDS-PAGE analysis showed high degree of protein polymerization for meat exposed to light, compared to the other samples. Light exposure induced reducible (disulfide) and non-reducible cross-links, while mainly disulfides were formed in meat stored in the dark. Light exposure was responsible for 58% loss of free thiols (Cys residues). No significant loss of other amino acid residues was observed and none of the most common oxidation products of tryptophan, tyrosine, and phenylalanine were detected. Intrinsic fluorescence measurements of tryptophan showed 27% loss in samples exposed to light, which was ascribed to loss of protein solubility via protein polymerization rather than tryptophan oxidation. Protein carbonyls were mainly detected in forced oxidized samples at Day 0.
    Matched MeSH terms: Disulfides/chemistry
  4. Synthesis of symmetrical bis-Schiff base-disulfide hybrids as highly effective anti-leishmanial agents
    Taha M, Sain AA, Ali M, Anouar EH, Rahim F, Ismail NH, et al.
    Bioorg Chem, 2020 06;99:103819.
    PMID: 32325334 DOI: 10.1016/j.bioorg.2020.103819
    Leishmaniasis has affected a wider part of population around the globe. Most often, the existing regiments to battle against leishmaniasis are inadequate and limited. In our ongoing efforts to develop new leishmanicidal agents, we have synthesized a series of novel and symmetrical bis-Schiff base-disulfide hybrids 1-27. Intermediate disulfide was synthesized from corresponding 2-aminothiol followed by reacting the coupled adduct with various aromatic aldehydes. All these compounds showed outstanding inhibition when compared with standard (Table 1). Out of twenty seven analogues, twenty two analogues i.e. 1-5, 7-13, 17-21, 23-27 analogues showed excellent inhibitory potential with EC50 values ranging from 0.010 ± 0.00 to 0.096 ± 0.01 μM while five compounds i.e. 6, 14-16, and 22 showed good inhibitory potential with EC50 values ranging from 0.10 ± 0.00 to 0.137 ± 0.01 μM when compared with the standard Amphotericin B. Structure-activity relationship has been established while molecular docking studies were performed to pin the binding interaction of active molecules. This study will help to develop new antileishmanial lead compounds.
    Matched MeSH terms: Disulfides/chemistry
  5. Synthesis of novel disulfide and sulfone hybrid scaffolds as potent β-glucuronidase inhibitor
    Taha M, Ismail NH, Imran S, Wadood A, Rahim F, Al Muqarrabin LM, et al.
    Bioorg Chem, 2016 10;68:15-22.
    PMID: 27414468 DOI: 10.1016/j.bioorg.2016.07.002
    Novel series of disulfide and sulfone hybrid analogs (1-20) were synthesized and characterized through EI-MS and (1)H NMR and evaluated for β-glucuronidase inhibitory potential. All synthesized analogs except 13 and 15 showed excellent β-glucuronidase inhibitory potential with IC50 value ranging in between 2.20-88.16μM as compared to standard d-saccharic acid 1,4 lactone (48.4±1.25μM). Analogs 19, 16, 4, 1, 17, 6, 10, 3, 18, 2, 11, 14 and 5 showed many fold potent activity against β-glucuronidase inhibitor. Structure activity relationship showed that substitution of electron withdrawing groups at ortho as well as para position on phenyl ring increase potency. Electron withdrawing groups at meta position on phenyl ring showed slightly low potency as compared to ortho and para position. The binding interactions were confirmed through molecular docking studies.
    Matched MeSH terms: Disulfides/chemistry
  6. Current and future envision on developing biosensors aided by 2D molybdenum disulfide (MoS2) productions
    Dalila R N, Md Arshad MK, Gopinath SCB, Norhaimi WMW, Fathil MFM
    Biosens Bioelectron, 2019 May 01;132:248-264.
    PMID: 30878725 DOI: 10.1016/j.bios.2019.03.005
    Two-dimensional (2D) layered nanomaterials have triggered an intensive interest due to the fascinating physiochemical properties with the exceptional physical, optical and electrical characteristics that transpired from the quantum size effect of their ultra-thin structure. Among the family of 2D nanomaterials, molybdenum disulfide (MoS2) features distinct characteristics related to the existence of direct energy bandgap, which significantly lowers the leakage current and surpasses other 2D materials. In this overview, we expatiate the novel strategies to synthesize MoS2 that cover techniques such as liquid exfoliation, chemical vapour deposition, mechanical exfoliation, hydrothermal reaction, and Van Der Waal epitaxial growth on the substrate. We extend the discussion on the recent progress in biosensing applications of the produced MoS2, highlighting the important surface-to-volume of ultrathin MoS2 structure, which enhances the overall performance of the devices. Further, envisioned the missing piece with the current MoS2-based biosensors towards developing the future strategies.
    Matched MeSH terms: Disulfides/chemistry*
  7. Fulltext Synthesis, characterisation, and evaluation of a cross-linked disulphide amide-anhydride-containing polymer based on cysteine for colonic drug delivery
    Lim V, Peh KK, Sahudin S
    Int J Mol Sci, 2013;14(12):24670-91.
    PMID: 24351841 DOI: 10.3390/ijms141224670
    The use of disulphide polymers, a low redox potential responsive delivery, is one strategy for targeting drugs to the colon so that they are specifically released there. The objective of this study was to synthesise a new cross-linked disulphide-containing polymer based on the amino acid cysteine as a colon drug delivery system and to evaluate the efficiency of the polymers for colon targeted drug delivery under the condition of a low redox potential. The disulphide cross-linked polymers were synthesised via air oxidation of 1,2-ethanedithiol and 3-mercapto-N-2-(3-mercaptopropionamide)-3-mercapto propionic anhydride (trithiol monomers) using different ratio combinations. Four types of polymers were synthesised: P10, P11, P151, and P15. All compounds synthesised were characterised by NMR, IR, LC-MS, CHNS analysis, Raman spectrometry, SEM-EDX, and elemental mapping. The synthesised polymers were evaluated in chemical reduction studies that were performed in zinc/acetic acid solution. The suitability of each polymer for use in colon-targeted drug delivery was investigated in vitro using simulated conditions. Chemical reduction studies showed that all polymers were reduced after 0.5-1.0 h, but different polymers had different thiol concentrations. The bacterial degradation studies showed that the polymers were biodegraded in the anaerobic colonic bacterial medium. Degradation was most pronounced for polymer P15. This result complements the general consensus that biodegradability depends on the swellability of polymers in an aqueous environment. Overall, these results suggest that the cross-linked disulphide-containing polymers described herein could be used as coatings for drugs delivered to the colon.
    Matched MeSH terms: Disulfides/chemistry*
  8. Surface active complexes formed between keratin polypeptides and ionic surfactants
    Pan F, Lu Z, Tucker I, Hosking S, Petkov J, Lu JR
    J Colloid Interface Sci, 2016 Dec 15;484:125-134.
    PMID: 27599381 DOI: 10.1016/j.jcis.2016.08.082
    Keratins are a group of important proteins in skin and hair and as biomaterials they can provide desirable properties such as strength, biocompatibility, and moisture regaining and retaining. The aim of this work is to develop water-soluble keratin polypeptides from sheep wool and then explore how their surface adsorption behaves with and without surfactants. Successful preparation of keratin samples was demonstrated by identification of the key components from gel electrophoresis and the reproducible production of gram scale samples with and without SDS (sodium dodecylsulphate) during wool fibre dissolution. SDS micelles could reduce the formation of disulphide bonds between keratins during extraction, reducing inter-molecular crosslinking and improving keratin polypeptide solubility. However, Zeta potential measurements of the two polypeptide batches demonstrated almost identical pH dependent surface charge distributions with isoelectric points around pH 3.5, showing complete removal of SDS during purification by dialysis. In spite of different solubility from the two batches of keratin samples prepared, very similar adsorption and aggregation behavior was revealed from surface tension measurements and dynamic light scattering. Mixing of keratin polypeptides with SDS and C12TAB (dodecyltrimethylammonium bromide) led to the formation of keratin-surfactant complexes that were substantially more effective at reducing surface tension than the polypeptides alone, showing great promise in the delivery of keratin polypeptides via the surface active complexes. Neutron reflection measurements revealed the coexistence of surfactant and keratin polypeptides at the interface, thus providing the structural support to the observed surface tension changes associated with the formation of the surface active complexes.
    Matched MeSH terms: Disulfides/chemistry
  9. Biocompatible disulphide cross-linked sodium alginate derivative nanoparticles for oral colon-targeted drug delivery
    Ayub AD, Chiu HI, Mat Yusuf SNA, Abd Kadir E, Ngalim SH, Lim V
    Artif Cells Nanomed Biotechnol, 2019 Dec;47(1):353-369.
    PMID: 30691309 DOI: 10.1080/21691401.2018.1557672
    The application of layer-by-layer (LbL) approach on nanoparticle surface coating improves the colon-specific drug delivery of insoluble drugs. Here, we aimed to formulate a self-assembled cysteamine-based disulphide cross-linked sodium alginate with LbL self-assembly to improve the delivery of paclitaxel (PCX) to colonic cancer cells. Cysteamine was conjugated to the backbone of oxidized SA to form a core of self-assembled disulphide cross-linked nanospheres. P3DL was selected for PCX loading and fabricated LbL with poly(allylamine hydrochloride) (PAH) and poly(4-styrenesulfonic acid-co-maleic acid) sodium salt (PSSCMA) resulting from characterization and drug release studies. P3DL-fabricated PCX-loaded nanospheres (P3DL/PAH/PSSCMA) exhibited an encapsulation efficiency of 77.1% with cumulative drug release of 45.1%. Dynamic light scattering analysis was reported at 173.6 ± 2.5 nm with polydispersity index of 0.394 ± 0.105 (zeta potential= -58.5 mV). P3DL/PAH/PSSCMA demonstrated a pH-dependent swelling transition; from pH 1 to 7 (102.2% increase). The size increased by 33.0% in reduction response study after incubating with 10 mM glutathione (day 7). HT-29 cells showed high viabilities (86.7%) after treatment with the fabricated nanospheres at 0.8 µg/mL. Cellular internalization was successful with more than 70.0% nanospheres detected in HT-29 cells. Therefore, this fabricated nanospheres may be considered as potential nanocarriers for colon cancer-targeted chemotherapeutic drug delivery.
    Matched MeSH terms: Disulfides/chemistry*
  10. Fulltext Prevailing Knowledge on the Bioavailability and Biological Activities of Sulphur Compounds from Alliums: A Potential Drug Candidate
    Subramanian MS, Nandagopal Ms G, Amin Nordin S, Thilakavathy K, Joseph N
    Molecules, 2020 Sep 09;25(18).
    PMID: 32916777 DOI: 10.3390/molecules25184111
    Allium sativum (garlic) is widely known and is consumed as a natural prophylactic worldwide. It produces more than 200 identified chemical compounds, with more than 20 different kinds of sulfide compounds. The sulfide compounds particularly are proven to contribute to its various biological roles and pharmacological properties such as antimicrobial, antithrombotic, hypoglycemic, antitumour, and hypolipidemic. Therefore, it is often referred as disease-preventive food. Sulphur-containing compounds from A. sativum are derivatives of S-alkenyl-l-cysteine sulfoxides, ajoene molecules, thiosulfinates, sulfides, and S-allylcysteine. This review presents an overview of the water-soluble and oil-soluble sulphur based phytochemical compounds present in garlic, highlighting their mechanism of action in treating various health conditions. However, its role as a therapeutic agent should be extensively studied as it depends on factors such as the effective dosage and the suitable method of preparation.
    Matched MeSH terms: Disulfides/chemistry
  11. Generation of soluble, disulfide-rich JEV NS1 protein recognizable by anti-NS1 antibodies through a simplified, in vitro refolding approach
    Chong HY, Leow CY, Leow CH
    Int J Biol Macromol, 2021 Aug 31;185:485-493.
    PMID: 34174313 DOI: 10.1016/j.ijbiomac.2021.06.146
    Co-existence of Japanese Encephalitis virus (JEV) with highly homologous antigenic epitopes results in antibody-based serodiagnosis being inaccurate at detecting and distinguishing JEV from other flaviviruses. This often causes misdiagnosis and inefficient treatments of flavivirus infection. Generation of JEV NS1 protein remains a challenge as it is notably expressed in the form of inactive aggregates known as inclusion bodies using bacterial expression systems. This study evaluated two trxB and gor E. coli strains in producing soluble JEV NS1 via a cold-shock expression system. High yield of JEV NS1 inclusion bodies was produced using cold-shocked expression system. Subsequently, a simplified yet successful approach in generating soluble, active JEV NS1 protein through solubilization, purification and in vitro refolding of JEV NS1 protein from inclusion bodies was developed. A step-wise dialysis refolding approach was used to facilitate JEV NS1 refolding. The authenticity of the refolded JEV NS1 was confirmed by specific antibody binding on indirect ELISA commercial anti-NS1 antibodies which showed that the refolded JEV NS1 was highly immunoreactive. This presented approach is cost-effective, and negates the need for mammalian or insect cell expression systems in order to synthesize this JEV NS1 protein of important diagnostic and therapeutic relevance in Japanese Encephalitis disease.
    Matched MeSH terms: Disulfides/chemistry
  12. Molybdenum disulfide-gold nanoparticle nanocomposite in field-effect transistor back-gate for enhanced C-reactive protein detection
    Dalila NR, Arshad MKM, Gopinath SCB, Nuzaihan MNM, Fathil MFM
    Mikrochim Acta, 2020 10 05;187(11):588.
    PMID: 33015730 DOI: 10.1007/s00604-020-04562-7
    Nanofabricated gold nanoparticles (Au-NPs) on MoS2 nanosheets (Au-NPs/MoS2) in back-gated field-effect transistor (BG-FET) are presented, which acts as an efficient semiconductor device for detecting a low concentration of C-reactive protein (C-RP). The decorated nanomaterials lead to an enhanced electron conduction layer on a 100-μm-sized transducing channel. The sensing surface was characterized by Raman spectroscopy, ultraviolet-visible spectroscopy (UV-Vis), atomic force microscopy (AFM), scanning electron microscopy (SEM), and high-power microscopy (HPM). The BG-FET device exhibits an excellent limit of detection of 8.38 fg/mL and a sensitivity of 176 nA/g·mL-1. The current study with Au-NPs/MoS2 BG-FET displays a new potential biosensing technology; especially for integration into complementary metal oxide (CMOS) technology for hand-held future device application.
    Matched MeSH terms: Disulfides/chemistry
  13. Fulltext Wheat Germ Agglutinin-Conjugated Disulfide Cross-Linked Alginate Nanoparticles as a Docetaxel Carrier for Colon Cancer Therapy
    Chiu HI, Lim V
    Int J Nanomedicine, 2021;16:2995-3020.
    PMID: 33911862 DOI: 10.2147/IJN.S302238
    PURPOSE: In chemotherapy, oral administration of drug is limited due to lack of drug specificity for localized colon cancer cells. The inability of drugs to differentiate cancer cells from normal cells induces side effects. Colonic targeting with polymeric nanoparticulate drug delivery offers high potential strategies for delivering hydrophobic drugs and fewer side effects to the target site. Disulfide cross-linked polymers have recently acquired high significance due to their potential to degrade in reducing colon conditions while resisting the upper gastrointestinal tract's hostile environment. The goal of this project is, therefore, to develop pH-sensitive and redox-responsive fluorescein-labeled wheat germ agglutinin (fWGA)-mounted disulfide cross-linked alginate nanoparticles (fDTP2) directly targeting docetaxel (DTX) in colon cancer cells.

    METHODS: fDTP2 was prepared by mounting fWGA on DTX-loaded nanoparticles (DTP2) using the two-step carbodiimide method. Morphology of fDTP2 was examined using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Dynamic light scattering (DLS) study was carried out to determine the mean diameter, polydispersity index (PDI) and zeta potential of fDTP2. Cellular uptake efficiency was examined using fluorescence microplate reader. Biocompatibility and active internalization of fDTP2 were conducted on HT-29.

    RESULTS: fDTP2 was found to exhibit a DTX loading efficiency of 19.3%. SEM and TEM tests revealed spherical nanoparticles. The in vitro DTX release test showed a cumulative release of 54.7%. From the DLS study, fDTP2 reported a 277.7 nm mean diameter with PDI below 0.35 and -1.0 mV zeta potential. HT-29 which was fDTP2-treated demonstrated lower viability than L929 with a half maximal inhibitory concentration (IC50) of 34.7 µg/mL. HT-29 (33.4%) internalized fDTP2 efficiently at 2 h incubation. The study on HT-29 active internalization of nanoparticles through fluorescence and confocal imaging indicated such.

    CONCLUSION: In short, fDTP2 demonstrated promise as a colonic drug delivery DTX transporter.

    Matched MeSH terms: Disulfides/chemistry
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