Sagacious Epitope Selection for Vaccines, and Both Antibody-Based Therapeutics and Diagnostics: Tips From Virology and Oncology

The target of an antibody plays a significant role in the success of antibody-based therapeutics and diagnostics, and to an extent, that of vaccine development. This importance is focussed on the target binding site – epitope, where epitope selection as a part of design thinking beyond traditional antigen selection using whole cell or whole protein immunisation can positively impact success. With purified recombinant protein production and peptide synthesis to display limited/selected epitopes, intrinsic factors that can affect the functioning of resulting antibodies can be more easily selected for. Many of these factors stem from the location of the epitope that can affect accessibility of the antibody to the epitope at a cellular or molecular level, direct inhibition of target antigen activity, conservation of function despite escape mutations, and even non-competitive inhibition sites. Through the incorporation of novel computational methods for predicting antigen changes to model-informed drug discovery and development, superior vaccines and antibody-based therapeutics or diagnostics can now be more easily designed to mitigate failures. With detailed examples, this review highlights the new opportunities, factors and methods of predicting antigenic changes for consideration in sagacious epitope selection.

Sagacious Epitope Selection for Vaccines, and Both Antibody-Based Therapeutics and Diagnostics: Tips From Virology and Oncology

The target of an antibody plays a significant role in the success of antibody-based therapeutics and diagnostics, and to an extent, that of vaccine development. This importance is focussed on the target binding site – epitope, that sagacious epitope selection in a form of design thinking beyond traditional antigen selection using whole cell or whole protein immunisation can positively improve success. Intrinsic factors that can affect the functioning of resulting antibodies can be more easily selected for with purified recombinant protein production and peptide synthesis to display limited/selected epitopes. Many of these factors stem from the location of the epitope that can affect the accessibility of the antibody to the epitope at a cellular or molecular level, direct inhibition of target antigen activity, conservation of function despite escape mutations, and even non-competitive inhibition sites. Through the incorporation of novel computational methods for predicting antigen changes to model-informed drug design development, superior vaccines and antibody-based therapeutics or diagnostics can now be more easily designed, mitigating failures. With detailed examples, this review highlights the new opportunities, factors and methods of predicting antigenic changes for consideration in sagacious epitope selection.

miR-124-3p enhances dendritic cell-mediated anti-tumor immunity by targeting CYLD/4-1BBL pathway

Objective: To investigate miR-124-3p regulation of DC-mediated immune response via CYLD/4-1BBL pathway, and the inhibitory effect of miR-124-3p on lung cancer.Methods: DCs were cultured and amplified in vitro, and then transfected with miR-124-3p mimic, miR-124-3P inhibitor, or siRNA CYLD. Double luciferase reporter genes were used to detect the target relationship between miR-124-3p and CYLD. qRT-PCR and western blotting were used to detect the expression levels of CYLD and 4-1BBL. Flow cytometry was used to assess the proliferation rate of CD4+ T cells co-cultured with untransfected DCs and those transfected with miR-124-3p mimic or miR-124-3p inhibitor. C57BL/6 tumor bearing mice, implanted with LL/2 lung adenocarcinoma cells, were administered DCs transfected with the miR-124-3p mimic or untransfected DCs. The tumor size and weight of mice were then measured. Results: miR-124-3p and CYLD3’UTR contained target-binding site, and overexpression of miR-124-3p enhanced the expression of CYLD and 4-1BBL. CD4+ T cells co-cultured with miR-124-3p mimic-transfected DCs showed significantly increased proliferation. In tumor-bearing mice, tumor inhibition rate was 73.5%, and tumor volume and weight were significantly decreased after the administration of DCs containing the miR-124-3p mimic.Conclusions: The expression of CYLD was regulated by miR-124-3p, which, in turn, increased the expression of 4-1BBL. miR-124-3p regulated DCs function via CYLD/4-1BBL cascade. miR-124-3p plays important roles in DCs-induced T cells, thereby enhancing anti-tumor immunity.

Structure-based de novo drug design using 3D deep generative models

DeepLigBuilder, a novel deep generative model for structure-based de novo drug design, directly generates 3D structures of drug-like compounds in the target binding site.

Parallelization of Molecular Docking: A Review

Molecular docking, as one of the widely used virtual screening methods, aims to predict the binding-conformations of small molecule ligands to the appropriate target binding site. Because of the computational complexity and the arrival of the big data era, molecular docking requests High- Performance Computing (HPC) to improve its performance and accuracy. We discuss, in detail, the advances in accelerating molecular docking software in parallel, based on the different common HPC platforms, respectively. Not only the existing suitable programs have been optimized and ported to HPC platforms, but also many novel parallel algorithms have been designed and implemented. This review focuses on the techniques and methods adopted in parallelizing docking software. Where appropriate, we refer readers to exemplary case studies.

On the Importance of Hydrodynamic Interactions in the Stepping Kinetics of Kinesin

Conventional kinesin walks by a hand-over-hand mechanism on the microtubule (MT) by taking ∼ 8nmdiscrete steps, and consumes one ATP molecule per step. The time needed to complete a single step is on the order of twenty microseconds. We show, using simulations of a coarse-grained model of the complex containing the two motor heads, the MT, and the coiled coil that in order to obtain quantitative agreement with experiments for the stepping kinetics hydrodynamic interactions (HI) have to be included. In simulations without hydrodynamic interactions spanning nearly twenty microseconds not a single step was completed in hundred trajectories. In sharp contrast, nearly 14% of the steps reached the target binding site within 6 microseconds when HI were included. Somewhat surprisingly, there are qualitative differences in the diffusion pathways in simulations with and without HI. The extent of movement of the trailing head of kinesin on the MT during the diffusion stage of stepping is considerably greater in simulations with HI than in those without HI. Our results suggest that inclusion of HI is crucial in the accurate description of motility of other motors as well.