The Molecular Mechanisms and Rational Design of Anti-Diabetic Vanadium Compounds

2015 ◽  
Vol 16 (8) ◽  
pp. 811-822 ◽  
Author(s):  
Xia Niu ◽  
Ruyue Xiao ◽  
Na Wang ◽  
Ziwei Wang ◽  
Yue Zhang ◽  
...  
Keyword(s):  
Rational Design ◽  
Molecular Mechanisms ◽  
Vanadium Compounds

Aberrant protein glycosylation in cancer: implications in targeted therapy

2021 ◽  
Author(s):  
Joana G. Rodrigues ◽  
Henrique O. Duarte ◽  
Celso A. Reis ◽  
Joana Gomes
Keyword(s):  
Targeted Therapy ◽  
Tumour Cell ◽  
Rational Design ◽  
Molecular Mechanisms ◽  
Clinical Performance ◽  
Therapeutic Strategies ◽  
Protein Glycosylation ◽  
Immune Checkpoints ◽  
Immunosuppressive Microenvironment ◽  
The Impact

Aberrant cell surface glycosylation signatures are currently known to actively drive the neoplastic transformation of healthy cells. By disrupting the homeostatic functions of their protein carriers, cancer-associated glycans mechanistically underpin several molecular hallmarks of human malignancy. Furthermore, such aberrant glycan structures play key roles in the acquisition of molecular resistance to targeted therapeutic agents, which compromises their clinical efficacy, by modulating tumour cell aggressiveness and supporting the establishment of an immunosuppressive microenvironment. Recent advances in the study of the tumour cell glycoproteome have unravelled previously elusive molecular mechanisms of therapeutic resistance, guided the rational design of novel personalized therapeutic strategies, and may further improve the clinical performance of currently approved anti-cancer targeted agents. In this review, we highlight the impact of glycosylation in cancer targeted therapy, with particular focus on receptor tyrosine kinase-targeted therapy, immune checkpoints blockade therapy, and current developments on therapeutic strategies directed to glycan-binding proteins and other innovative glycan therapeutic strategies.

scholarly journals Main Structural Targets for Engineering Lipase Substrate Specificity

Catalysts ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 747
Author(s):  
Samah Hashim Albayati ◽  
Malihe Masomian ◽  
Siti Nor Hasmah Ishak ◽  
Mohd Shukuri bin Mohamad Ali ◽  
Adam Leow Thean ◽  
...  
Keyword(s):  
Substrate Specificity ◽  
Rational Design ◽  
Molecular Mechanisms ◽  
Experimental Studies ◽  
Random Mutagenesis ◽  
Binding Pocket ◽  
Amino Acid Sequences ◽  
Site Directed Mutagenesis ◽  
Saturation Mutagenesis ◽  
Process Conditions

Microbial lipases represent one of the most important groups of biotechnological biocatalysts. However, the high-level production of lipases requires an understanding of the molecular mechanisms of gene expression, folding, and secretion processes. Stable, selective, and productive lipase is essential for modern chemical industries, as most lipases cannot work in different process conditions. However, the screening and isolation of a new lipase with desired and specific properties would be time consuming, and costly, so researchers typically modify an available lipase with a certain potential for minimizing cost. Improving enzyme properties is associated with altering the enzymatic structure by changing one or several amino acids in the protein sequence. This review detailed the main sources, classification, structural properties, and mutagenic approaches, such as rational design (site direct mutagenesis, iterative saturation mutagenesis) and direct evolution (error prone PCR, DNA shuffling), for achieving modification goals. Here, both techniques were reviewed, with different results for lipase engineering, with a particular focus on improving or changing lipase specificity. Changing the amino acid sequences of the binding pocket or lid region of the lipase led to remarkable enzyme substrate specificity and enantioselectivity improvement. Site-directed mutagenesis is one of the appropriate methods to alter the enzyme sequence, as compared to random mutagenesis, such as error-prone PCR. This contribution has summarized and evaluated several experimental studies on modifying the substrate specificity of lipases.

scholarly journals Structural Insights into the Mechanism of a Nanobody That Stabilizes PAI-1 and Modulates Its Activity

2020 ◽  
Vol 21 (16) ◽  
pp. 5859
Author(s):  
Machteld Sillen ◽  
Stephen D. Weeks ◽  
Sergei V. Strelkov ◽  
Paul J. Declerck
Keyword(s):  
Rational Design ◽  
Therapeutic Strategy ◽  
Molecular Mechanisms ◽  
Biochemical Characterization ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
Plasminogen Activator Inhibitor 1 ◽  
Structural Insights ◽  
Activator Inhibitor ◽  
Pai 1

Plasminogen activator inhibitor-1 (PAI-1) is the main physiological inhibitor of tissue-type (tPA) and urokinase-type (uPA) plasminogen activators (PAs). Apart from being critically involved in fibrinolysis and wound healing, emerging evidence indicates that PAI-1 plays an important role in many diseases, including cardiovascular disease, tissue fibrosis, and cancer. Targeting PAI-1 is therefore a promising therapeutic strategy in PAI-1 related pathologies. Despite ongoing efforts no PAI-1 inhibitors were approved to date for therapeutic use in humans. A better understanding of the molecular mechanisms of PAI-1 inhibition is therefore necessary to guide the rational design of PAI-1 modulators. Here, we present a 1.9 Å crystal structure of PAI-1 in complex with an inhibitory nanobody VHH-s-a93 (Nb93). Structural analysis in combination with biochemical characterization reveals that Nb93 directly interferes with PAI-1/PA complex formation and stabilizes the active conformation of the PAI-1 molecule.

scholarly journals Gold Nanomaterials and Bone/Cartilage Tissue Engineering: Biomedical Applications and Molecular Mechanisms

2021 ◽  
Vol 9 ◽  
Author(s):  
Yifeng Shi ◽  
Xuyao Han ◽  
Shuang Pan ◽  
Yuhao Wu ◽  
Yuhan Jiang ◽  
...  
Keyword(s):  
Tissue Engineering ◽  
Biomedical Applications ◽  
Rational Design ◽  
Molecular Mechanisms ◽  
Materials Science ◽  
Rapid Development ◽  
Cartilage Tissue Engineering ◽  
Cartilage Tissue ◽  
Gold Nanomaterials ◽  
And Cartilage

Recently, as our population increasingly ages with more pressure on bone and cartilage diseases, bone/cartilage tissue engineering (TE) have emerged as a potential alternative therapeutic technique accompanied by the rapid development of materials science and engineering. The key part to fulfill the goal of reconstructing impaired or damaged tissues lies in the rational design and synthesis of therapeutic agents in TE. Gold nanomaterials, especially gold nanoparticles (AuNPs), have shown the fascinating feasibility to treat a wide variety of diseases due to their excellent characteristics such as easy synthesis, controllable size, specific surface plasmon resonance and superior biocompatibility. Therefore, the comprehensive applications of gold nanomaterials in bone and cartilage TE have attracted enormous attention. This review will focus on the biomedical applications and molecular mechanism of gold nanomaterials in bone and cartilage TE. In addition, the types and cellular uptake process of gold nanomaterials are highlighted. Finally, the current challenges and future directions are indicated.

scholarly journals Genetic optimisation of bacteria-induced calcite precipitation in Bacillus subtilis

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Timothy D. Hoffmann ◽  
Kevin Paine ◽  
Susanne Gebhard
Keyword(s):  
Bacillus Subtilis ◽  
Cell Surface ◽  
Rational Design ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Contributing Factors ◽  
Calcite Precipitation ◽  
Nucleation Sites ◽  
Nickel Uptake ◽  
Extracellular Substances

Abstract Background Microbially induced calcite precipitation (MICP) is an ancient property of bacteria, which has recently gained considerable attention for biotechnological applications. It occurs as a by-product of bacterial metabolism and involves a combination of chemical changes in the extracellular environment, e.g. pH increase, and presence of nucleation sites on the cell surface or extracellular substances produced by the bacteria. However, the molecular mechanisms underpinning MICP and the interplay between the contributing factors remain poorly understood, thus placing barriers to the full biotechnological and synthetic biology exploitation of bacterial biomineralisation. Results In this study, we adopted a bottom-up approach of systematically engineering Bacillus subtilis, which has no detectable intrinsic MICP activity, for biomineralisation. We showed that heterologous production of urease can induce MICP by local increases in extracellular pH, and this can be enhanced by co-expression of urease accessory genes for urea and nickel uptake, depending on environmental conditions. MICP can be strongly enhanced by biofilm-promoting conditions, which appeared to be mainly driven by production of exopolysaccharide, while the protein component of the biofilm matrix was dispensable. Attempts to modulate the cell surface charge of B. subtilis had surprisingly minor effects, and our results suggest this organism may intrinsically have a very negative cell surface, potentially predisposing it for MICP activity. Conclusions Our findings give insights into the molecular mechanisms driving MICP in an application-relevant chassis organism and the genetic elements that can be used to engineer de novo or enhanced biomineralisation. This study also highlights mutual influences between the genetic drivers and the chemical composition of the surrounding environment in determining the speed, spatial distribution and resulting mineral crystals of MICP. Taken together, these data pave the way for future rational design of synthetic precipitator strains optimised for specific applications.

scholarly journals Omics-Based Interaction Framework – a systems model to reveal molecular drivers of synergy

2020 ◽  
Author(s):  
Jezreel Pantaleón García ◽  
Vikram V. Kulkarni ◽  
Tanner C. Reese ◽  
Shradha Wali ◽  
Saima J. Wase ◽  
...  
Keyword(s):  
Influenza A ◽  
Rational Design ◽  
Molecular Mechanisms ◽  
Molecular Clusters ◽  
Biological Interactions ◽  
Combination Therapies ◽  
Experimental Conditions ◽  
Biologically Relevant ◽  
Proteomic Data ◽  
Systems Model

AbstractBioactive molecule library screening strategies may empirically identify effective combination therapies. However, without a systems theory to interrogate synergistic responses, the molecular mechanisms underlying favorable drug-drug interactions remain unclear, precluding rational design of combination therapies. Here, we introduce Omics-Based Interaction Framework (OBIF) to reveal molecular drivers of synergy through integration of statistical and biological interactions in supra-additive biological responses. OBIF performs full factorial analysis of feature expression data from single vs. dual factor exposures to identify molecular clusters that reveal synergy-mediating pathways, functions and regulators. As a practical demonstration, OBIF analyzed a therapeutic dyad of immunostimulatory small molecules that induces synergistic protection against influenza A pneumonia. OBIF analysis of transcriptomic and proteomic data identified biologically relevant, unanticipated cooperation between RelA and cJun that we subsequently confirmed to be required for the synergistic antiviral protection. To demonstrate generalizability, OBIF was applied to data from a diverse array of Omics platforms and experimental conditions, successfully identifying the molecular clusters driving their synergistic responses. Hence, OBIF is a phenotype-driven systems model that supports multiplatform exploration of synergy mechanisms.

scholarly journals Molecular mechanism of point mutation-induced Monopolar spindle 1 (Mps1/TTK) inhibitor resistance revealed by a comprehensive molecular modeling study

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e6299 ◽  
Author(s):  
Yan Han ◽  
Yungang Wu ◽  
Yi Xu ◽  
Wentao Guo ◽  
Na Zhang ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Rational Design ◽  
Md Simulation ◽  
Molecular Mechanisms ◽  
Point Mutations ◽  
Conformational Ensemble ◽  
Energy Calculation ◽  
Therapeutic Effects ◽  
Monopolar Spindle ◽  
Inhibitor Resistance

Background Monopolar spindle 1 (Mps1/TTK) is an apical dual-specificity protein kinase in the spindle assembly checkpoint (SAC) that guarantees accurate segregation of chromosomes during mitosis. High levels of Mps1 are found in various types of human malignancies, such as glioblastoma, osteosarcoma, hepatocellular carcinoma, and breast cancer. Several potent inhibitors of Mps1 exist, and exhibit promising activity in many cell cultures and xenograft models. However, resistance due to point mutations in the kinase domain of Mps1 limits the therapeutic effects of these inhibitors. Understanding the detailed resistance mechanism induced by Mps1 point mutations is therefore vital for the development of novel inhibitors against malignancies. Methods In this study, conventional molecular dynamics (MD) simulation and Gaussian accelerated MD (GaMD) simulation were performed to elucidate the resistance mechanisms of Cpd-5, a potent Mps1 inhibitor, induced by the four representative mutations I531M, I598F, C604Y, S611R. Results Our results from conventional MD simulation combined with structural analysis and free energy calculation indicated that the four mutations weaken the binding affinity of Cpd-5 and the major variations in structural were the conformational changes of the P-loop, A-loop and αC-helix. Energetic differences of per-residue between the WT system and the mutant systems indicated the mutations may allosterically regulate the conformational ensemble and the major variations were residues of Ile-663 and Gln-683, which located in the key loops of catalytic loop and A-loop, respectively. The large conformational and energetic differences were further supported by the GaMD simulations. Overall, these obtained molecular mechanisms will aid rational design of novel Mps1 inhibitors to combat inhibitor resistance.

scholarly journals Genetic Optimisation of Bacteria-Induced Calcite Precipitation in Bacillus subtilis

2021 ◽  
Author(s):  
Timothy D Hoffmann ◽  
Kevin Paine ◽  
Susanne Gebhard
Keyword(s):  
Bacillus Subtilis ◽  
Cell Surface ◽  
Rational Design ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Contributing Factors ◽  
Calcite Precipitation ◽  
Nucleation Sites ◽  
Nickel Uptake ◽  
Extracellular Substances

Background Microbially induced calcite precipitation (MICP) is an ancient property of bacteria, which has recently gained considerable attention for biotechnological applications. It occurs as a by-product of bacterial metabolism and involves a combination of chemical changes in the extracellular environment, e.g. pH increase, and presence of nucleation sites on the cell surface or extracellular substances produced by the bacteria. However, the molecular mechanisms underpinning MICP and the interplay between the contributing factors remain poorly understood, thus placing barriers to the full biotechnological and synthetic biology exploitation of bacterial biomineralisation. Results In this study, we adopted a bottom-up approach of systematically engineering Bacillus subtilis, which has no detectable intrinsic MICP activity, for biomineralisation. We showed that heterologous production of urease can induce MICP by local increases in extracellular pH, and this can be enhanced by co-expression of urease accessory genes for urea and nickel uptake, depending on environmental conditions. MICP can be strongly enhanced by biofilm-promoting conditions, which appeared to be mainly driven by production of exopolysaccharide, while the protein component of the biofilm matrix was dispensable. Attempts to modulate the cell surface charge of B. subtilis had surprisingly minor effects, and our results suggest this organism may intrinsically have a very negative cell surface, potentially predisposing it for MICP activity. Conclusions Our findings give insights into the molecular mechanisms driving MICP in an application-relevant chassis organism and the genetic elements that can be used to engineer de novo or enhanced biomineralisation. This study also highlights mutual influences between the genetic drivers and the chemical composition of the surrounding environment in determining the speed, spatial distribution and resulting mineral crystals of MICP. Taken together, these data pave the way for future rational design of synthetic precipitator strains optimised for specific applications.

scholarly journals A Review of the Current Knowledge of Thermal Stability of Anthocyanins and Approaches to Their Stabilization to Heat

Antioxidants ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1337
Author(s):  
Simona Oancea
Keyword(s):  
Thermal Stability ◽  
Rational Design ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Scientific Progress ◽  
Bioactive Molecules ◽  
Environmental Stability ◽  
Published Data ◽  
Thermal Stability Of ◽  
Anthocyanin Degradation

Anthocyanins are colored valuable biocompounds, of which extraction increases globally, although functional applications are restrained by their limited environmental stability. Temperature is a critical parameter of food industrial processing that impacts on the food matrix, particularly affecting heat-sensitive compounds such as anthocyanins. Due to the notable scientific progress in the field of thermal stability of anthocyanins, an analytical and synthetic integration of published data is required. This review focuses on the molecular mechanisms and the kinetic parameters of anthocyanin degradation during heating, both in extracts and real food matrices. Several kinetic models (Arrhenius, Eyring, Ball) of anthocyanin degradation were studied. Crude extracts deliver more thermally stable anthocyanins than purified ones. A different anthocyanin behavior pattern within real food products subjected to thermal processing has been observed due to interactions with some nutrients (proteins, polysaccharides). The most recent studies on the stabilization of anthocyanins by linkages to other molecules using classical and innovative methods are summarized. Ensuring appropriate thermal conditions for processing anthocyanin-rich food will allow a rational design for the future development of stable functional products, which retain these bioactive molecules and their functionalities to a great extent.

scholarly journals Potent germline-like monoclonal antibodies: Rapid identification of promising candidates for antibody-based antiviral therapy

2021 ◽  
Author(s):  
Xiaoyi Zhu ◽  
Fei Yu ◽  
Yanling Wu ◽  
Tianlei Ying
Keyword(s):  
Monoclonal Antibodies ◽  
Rational Design ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Somatic Hypermutation ◽  
Affinity Maturation ◽  
Human Mabs

Abstract Recent years, fully human monoclonal antibodies (mAbs) are making up an increasing share of the pharmaceutical market. However, to improve affinity and efficacy of antibodies, many somatic hypermutation could be introduced during affinity maturation, which cause several issues including safety and efficacy and limit their application in clinic. Here, we propose a special class of human mAbs with limited level of somatic mutations, referred to as germline-like mAbs. Remarkably, germline-like mAbs could have high affinity and potent neutralizing activity in vitro and in various animal models, despite lacking of extensive affinity maturation. Furthermore, the germline nature of these mAbs implies that they exhibit lower immunogenicity and can be elicited relatively fast in vivo compared with highly somatically mutated antibodies. In this review, we summarize germline-like mAbs with strong therapeutic and protection activity against various viruses that caused large-scale outbreaks in the last decade, including influenza virus H7N9, Zika virus (ZIKV), Dengue virus (DENV), Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We also illustrate underlying molecular mechanisms of these germline-like antibodies against viral infections from the structural and genetic perspective, thus providing insight into further development as therapeutic agents for treatment of infectious diseases and implication for rational design of effective vaccines.

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