Probing binding mechanism of interleukin-6 and olokizumab: in silico design of potential lead antibodies for autoimmune and inflammatory diseases

Computer-aided antibody engineering has been successful in the design of new biologics for disease diagnosis and therapeutic interventions. Interleukin-6 (IL-6), a well-recognized drug target for various autoimmune and inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, and psoriasis, was investigated in silico to design potential lead antibodies. Here, crystal structure of IL-6 along with monoclonal antibody olokizumab was explored to predict antigen–antibody (Ag???Ab)-interacting residues using DiscoTope, Paratome, and PyMOL. Tyr56, Tyr103 in heavy chain and Gly30, Ile31 in light chain of olokizumab were mutated with residues Ser, Thr, Tyr, Trp, and Phe. A set of 899 mutant macromolecules were designed, and binding affinity of these macromolecules to IL-6 was evaluated through Ag???Ab docking (ZDOCK, ClusPro, and Rosetta server), binding free-energy calculations using Molecular Mechanics/Poisson Boltzman Surface Area (MM/PBSA) method, and interaction energy estimation. In comparison to olokizumab, eight newly designed theoretical antibodies demonstrated better result in all assessments. Therefore, these newly designed macromolecules were proposed as potential lead antibodies to serve as a therapeutics option for IL-6-mediated diseases.     

Effect of tannery sludge amendments on the activity of soil enzymes and phytoremediation potential of two economically important cultivars of geranium (Pelargonium graveolens)

A field experiment was conducted to observe the effect of TS amendments on soil enzymes and phytoremediation potential of two economically important cultivars of geranium. Different doses of TS were applied in soil to examine threshold limit of HMs where geranium cultivars can be grown successfully in contaminated sites. Treatment variation significantly affected pH, EC, OC, N, P, K and HM content in soil after 50 days of incubation. After harvest, both cultivars were examined to assess the impact of various treatments on their fresh herb, dry matter, essential oil yield and HM accumulation. C/G ratio close to 1 was observed at 50 tha^?1 sludge treatment in both cultivars. Urease and β-glucosidase activities in soil were maximum at 50 tha^?1 whereas dehydrogenase and phosphatase activities were maximum at 100 tha^?1 in both cultivars. β-glucosidase, acid and alkaline phosphatase, urease and dehydrogenase activities were relatively high after 85 days over 45 days in both cultivars. Maximum metal uptake was found in roots of cv. Bourbon followed by leaves. Geranium was observed to be a good candidate for phytoremediation as it mitigates metal toxicity by root absorption and cv. Bourbon is better candidate for the same.     

5-Lipoxygenase as a drug target: A review on trends in inhibitors structural design,SAR and mechanism based approach

The most common inflammatory disease of the airways is asthma among children affecting around 235 million people worldwide. 5-Lipoxygenase (5-LOX) is a crucial enzyme which helps in the conversion of arachidonic acid (AA) to leukotrienes (LTs), the lipid mediators. It is associated with several inflammation related disorders such as asthma, allergy, and atherosclerosis. Therefore, it is considered as a promising target against inflammation and asthma. Currently, the only drug against 5-LOX which is available is Zileuton, while a few inhibitors are in clinical trial stages such as Atreleuton and Setileuton. So, there is a dire requirement in the area of progress of novel 5-LOX inhibitors which necessitates an understanding of their structure activity relationship and mode of action. In this review, novel 5-LOX inhibitors reported so far, their structural design, SAR and developmental strategies along with clinical updates are discussed over the last two decades.     

Unravelling the emerging threats of microplastics to agroecosystems

Reviews in Environmental Science and Bio/Technology - In the past few decades, pollution from microplastics has emerged as an important issue on a global scale. These plastic particles are mainly...     

Antiviral Activity of the Human Cathelicidin,LL-37, and Derived Peptides on Seasonal and Pandemic Influenza A Viruses

Human LL-37, a cationic antimicrobial peptide, was recently shown to have antiviral activity against influenza A virus (IAV) strains in vitro and in vivo. In this study we compared the anti-influenza activity of LL-37 with that of several fragments derived from LL-37. We first tested the peptides against a seasonal H3N2 strain and the mouse adapted H1N1 strain, PR-8. The N-terminal fragment, LL-23, had slight neutralizing activity against these strains. In LL-23V9 serine 9 is substituted by valine creating a continuous hydrophobic surface. LL-23V9 has been shown to have increased anti-bacterial activity compared to LL-23 and we now show slightly increased antiviral activity compared to LL-23 as well. The short central fragments, FK-13 and KR-12, which have anti-bacterial activity did not inhibit IAV. In contrast, a longer 20 amino acid central fragment of LL-37 (GI-20) had neutralizing activity similar to LL-37. None of the peptides inhibited viral hemagglutination or neuraminidase activity. We next tested activity of the peptides against a strain of pandemic H1N1 of 2009 (A/California/04/09/H1N1 or “Cal09”). Unexpectedly, LL-37 had markedly reduced activity against Cal09 using several cell types and assays of antiviral activity. A mutant viral strain containing just the hemagglutinin (HA) of 2009 pandemic H1N1 was inhibited by LL-37, suggested that genes other than the HA are involved in the resistance of pH1N1. In contrast, GI-20 did inhibit Cal09. In conclusion, the central helix of LL-37 incorporated in GI-20 appears to be required for optimal antiviral activity. The finding that GI-20 inhibits Cal09 suggests that it may be possible to engineer derivatives of LL-37 with improved antiviral properties.     

Dynamics of the Peripheral Membrane Protein P2 from Human Myelin Measured by Neutron Scattering—A Comparison between Wild-Type Protein and a Hinge Mutant

Myelin protein P2 is a fatty acid-binding structural component of the myelin sheath in the peripheral nervous system, and its function is related to its membrane binding capacity. Here, the link between P2 protein dynamics and structure and function was studied using elastic incoherent neutron scattering (EINS). The P38G mutation, at the hinge between the β barrel and the α-helical lid, increased the lipid stacking capacity of human P2 in vitro, and the mutated protein was also functional in cultured cells. The P38G mutation did not change the overall structure of the protein. For a deeper insight into P2 structure-function relationships, information on protein dynamics in the 10 ps to 1 ns time scale was obtained using EINS. Values of mean square displacements mainly from protein H atoms were extracted for wild-type P2 and the P38G mutant and compared. Our results show that at physiological temperatures, the P38G mutant is more dynamic than the wild-type P2 protein, especially on a slow 1-ns time scale. Molecular dynamics simulations confirmed the enhanced dynamics of the mutant variant, especially within the portal region in the presence of bound fatty acid. The increased softness of the hinge mutant of human myelin P2 protein is likely related to an enhanced flexibility of the portal region of this fatty acid-binding protein, as well as to its interactions with the lipid bilayer surface requiring conformational adaptations.     

16SrRNA sequencing of Dye decolorizing bacteria isolated from Soil

Dye׳s residues in textile effluents are hazardous for humans and animals health. Such pollutants can be degraded into non-harmful molecules using biological approaches that are considered cheaper and ecologically safer. Isolated 15 bacterial cultures from soil that could be used in biological system were showed decolorization capacity for Acid Green dye (33.9% to 94.0%) using thin layer chromatography and broth culture method. The most promising cultures (AMC3) to decolorize Acid green Dye (94.6%) was re-coded as NSDSUAM for submitting at IMTECH, Chandigarh for sequencing. The 16SrRNA sequencing suggested that it can be a variant of Pseudomonas geniculata (99.85% identical similarity) with difference of 2 base pairs to reference strain Pseudomonas geniculata ATCC 19374(T). Thus present study proposed dye decolorizing efficiency of the isolated strain of Pseudomonas geniculata that was previously unnoticed. The sequence is deposited in NCBI GenBank with the accession number {"type":"entrez-nucleotide","attrs":{"text":"KP238100","term_id":"745856746","term_text":"KP238100"}}KP238100.