The glycoprotein gp63– a potential pan drug target for developing new antileishmanial agents

Devsani, Namrata; Vemula, Divya; Bhandari, Vasundhra

doi:10.1016/j.biochi.2022.11.015

Cited by 4 publications

(3 citation statements)

References 63 publications

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“…It could be applied as a pathogenic factor in the rst phase of infection. This antigen can create immunity responses of CD4 + T cells and stimulate the expression of cytokines associated with Th1 and protect the intra-cell parasite, which is known as an indicator of protected immunity in Leishmaniasis (Devsani, Vemula et al 2023). KMP11 is an immunogenic antigen expressed in both promastigote and amastigote forms.…”

Section: Discussionmentioning

confidence: 99%

Design and evaluation of a novel multi-epitope antigen for evaluate the diagnostic immunity responses against Leishmania infantum infection

Hashemzadeh,

Bandehpour,

Kheirandish

et al. 2024

Preprint

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Background Leishmania infantum is the causative agent of visceral leishmaniasis in the Mediterranean region. The diagnosis of complex visceral leishmaniasis and delays in the diagnosis of the infection are associated with the death of patients. Proper diagnosis of infection is an important measure in controlling and preventing the disease. However, studies have shown that the accuracy of antigens used in current diagnostic tests is insufficient, for this reason, researchers are trying to identify multi-epitope antigens as diagnostic markers to increase the specificity and sensitivity of diagnostic tests. In this study, the design and expression of Leishmania infantum multi-epitope antigens were carried out in two parts of the structure design using bioinformatics tools and the laboratory part for the production of the recombinant protein. Materials and Methods The aim of this study was to design and computationally analyze and express Leishmania infantum multi-epitope antigens. In this study, nine antigenic proteins (CPB, H1, KMP11, GP63, HASPB, A2, K39, LACK, and PSA) were selected. Bioinformatics analyzes such as prediction of immune cell epitopes, design of recombinant structure, antigenicity, allergenicity, evaluation of physicochemical properties, solubility, prediction of secondary structure and tertiary structure, refinement and validation of 3D model structure and finally in silico cloning optimization of protein construct were performed. After synthesis of the designed recombinant gene fusion sequence in pUC57 cloning vector, its subcloning was performed in pET26b prokaryotic expression vector using BamHI/ HindIII restriction enzymes. The expression of recombinant multi-epitope antigen was performed in E. coli B (BL21) strain using IPTG inducer and confirmed by SDS-PAGE and western blotting techniques. Results The results of computational analysis showed that the complete structure, which is suitable for immunogenicity and is non-allergenic, was successfully cloned into pET-26b and expressed as a complete protein. Conclusion Finally, the protein was approved. Based on the expression of recombinant proteins and bioinformatics analysis, this structure can be studied in mouse models and its safety can be evaluated.

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Section: Discussionmentioning

confidence: 99%

Design and evaluation of a novel multi-epitope antigen for evaluate the diagnostic immunity responses against Leishmania infantum infection

Hashemzadeh,

Bandehpour,

Kheirandish

et al. 2024

Preprint

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“…The C-terminal domain and 25 amino acids long signal sequences are located at the C-terminal end for GPI attachment. Similarly to other zinc-proteases, the zinc ion is coordinated to the ε-nitrogen atoms of His264, His268, and His334 and the nitrogen and carboxyl oxygen of a glycine, similarly to other metalloproteinases. − …”

Section: Metalloproteasesmentioning

confidence: 99%

Metalloenzyme Inhibitors against Zoonotic Infections: Focus on Leishmania and Schistosoma

Rossi,

Tudino,

Carullo

et al. 2024

ACS Infect. Dis.

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The term "zoonosis" denotes diseases transmissible among vertebrate animals and humans. These diseases constitute a significant public health challenge, comprising 61% of human pathogens and causing an estimated 2.7 million deaths annually. Zoonoses not only affect human health but also impact animal welfare and economic stability, particularly in low-and middleincome nations. Leishmaniasis and schistosomiasis are two important neglected tropical diseases with a high prevalence in tropical and subtropical areas, imposing significant burdens on affected regions. Schistosomiasis, particularly rampant in sub-Saharan Africa, lacks alternative treatments to praziquantel, prompting concerns regarding parasite resistance. Similarly, leishmaniasis poses challenges with unsatisfactory treatments, urging the development of novel therapeutic strategies. Effective prevention demands a One Health approach, integrating diverse disciplines to enhance diagnostics and develop safer drugs. Metalloenzymes, involved in parasite biology and critical in different biological pathways, emerged in the last few years as useful drug targets for the treatment of human diseases. Herein we have reviewed recent reports on the discovery of inhibitors of metalloenzymes associated with zoonotic diseases like histone deacetylases (HDACs), carbonic anhydrase (CA), arginase, and heme-dependent enzymes.

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“…Despite several investigations into distinct classes of compounds to nd possible gp63 inhibitors, not a single one of them has advanced to the clinical stage [16]. Unquestionably the most virulent species, L. donovani is responsible for the majority of cases of visceral leishmaniasis (VL) worldwide [17]. Therefore, in order to discover potent inhibitors to ght leishmaniasis, our study focuses on Ldgp63.…”

Section: Introductionmentioning

confidence: 99%

Computational Exploration of gp63: Unlocking Potential Inhibitors for Leishmaniasis

Vemula,

Jayasurya,

Bhandari

2024

Preprint

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Leishmaniasis is an infection caused by protozoa of the genus Leishmania, which belongs to a neglected group of diseases. Limited treatment options and emerging drug resistance has contributed towards morbidity and mortality due to leishmaniasis. Therefore, exploring new therapeutic targets responsible for the pathogen's virulence is a priority to combat the disease. One of the contributing molecular factors to Leishmania virulence and pathogenesis is the metalloprotease glycoprotein 63 (gp63), also known as leishmanolysin or major surface protease (MSP). This metalloprotease is abundant on the parasite's surface in both promastigote and amastigote Leishmania stages. The present study focuses on finding the inhibitors of gp63 using the ChEMBL database, which includes a large, diverse set of 12,00,000 compounds. This study pipeline includes homology modeling, virtual screening, free energy analysis and molecular dynamic simulations to identify the with potential inhibitors of gp63, an important virulence factor of Leishmania species. Fourteen compounds were identified with good docking scores (-11 to -9 kcal/mol) compared to the control Gly2. The stability of the protein-ligand complex was later determined by free energy, which was computed using MM/GBSA. Moreover, molecular dynamic simulations validated the stability of the top seven compounds (Compound 2, Compound 3, Compound 6, Compound 7, Compound 9, Compound 10 and Compound 13 using parameters like root mean square deviation (RMSD), root mean square fluctuation (RMSF) and protein-ligand interactions. Thus, these compounds may serve as leads for further in-vitro studies in order to develop potential leishmaniasis chemotherapeutics.

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The glycoprotein gp63– a potential pan drug target for developing new antileishmanial agents

Cited by 4 publications

References 63 publications

Design and evaluation of a novel multi-epitope antigen for evaluate the diagnostic immunity responses against Leishmania infantum infection

Design and evaluation of a novel multi-epitope antigen for evaluate the diagnostic immunity responses against Leishmania infantum infection

Metalloenzyme Inhibitors against Zoonotic Infections: Focus on Leishmania and Schistosoma

Computational Exploration of gp63: Unlocking Potential Inhibitors for Leishmaniasis

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