Anti-Biofilm Molecules Targeting Functional Amyloids

The choice of an effective therapeutic strategy in the treatment of biofilm-related infections is a significant issue. Amyloids, which have been historically related to human diseases, are now considered to be prevailing structural components of the biofilm matrix in a wide range of bacteria. This assumption creates the potential for an exciting research area, in which functional amyloids are considered to be attractive targets for drug development to dissemble biofilm structures. The present review describes the best-characterized bacterial functional amyloids and focuses on anti-biofilm agents that target intrinsic and facultative amyloids. This study provides a better understanding of the different modes of actions of the anti-amyloid molecules to inhibit biofilm formation. This information can be further exploited to improve the therapeutic strategies to combat biofilm-related infections.

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Strategies for the identification of ubiquitin ligase inhibitors

Biochemical Society Transactions ◽

10.1042/bst0380132 ◽

2010 ◽

Vol 38 (1) ◽

pp. 132-136 ◽

Cited By ~ 25

Author(s):

Seth J. Goldenberg ◽

Jeffrey G. Marblestone ◽

Michael R. Mattern ◽

Benjamin Nicholson

Keyword(s):

Ubiquitin Ligase ◽

Therapeutic Target ◽

Therapeutic Strategy ◽

Ubiquitin Proteasome System ◽

Advantages And Disadvantages ◽

Wide Range ◽

Attractive Therapeutic Target ◽

Ubiquitin Proteasome ◽

Effective Therapeutic Strategy ◽

Protein Ligases

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Patent Insight into the Development of Therapeutic Strategies against Coronaviruses

The Open COVID Journal ◽

10.2174/2666958702101010093 ◽

2021 ◽

Vol 1 (1) ◽

pp. 93-100

Author(s):

Hai-Long Zhang ◽

Ai-Feng Zhou ◽

Yiqian Li

Keyword(s):

Therapeutic Strategy ◽

Vaccine Development ◽

Rna Viruses ◽

Therapeutic Strategies ◽

Peptide Drugs ◽

Leading Role ◽

Global Pandemic ◽

Effective Therapeutic Strategy ◽

Insight Into ◽

Development And Evolution

Coronaviruses are a group of RNA viruses, which cause diseases in humans. The emergence of COVID-19, has caused a global pandemic. It is focused on developing an effective therapeutic strategy against COVID-19. To better understand the development and evolution of therapeutic strategies against coronaviruses, we conducted US granted patents analysis. The results showed vaccines played a leading role in therapies against coronaviruses. Both attenuated vaccines and recombinant genetic vaccines were very important approaches in vaccine development against coronaviruses. It is not a rapid approach to develop peptide drugs against COVID-19 or future novel coronaviruses. The study was the first one to show the development and evolution in therapeutic strategies against coronaviruses based on patent insight. The present study provides a new insight into the development of therapeutic strategies against coronaviruses.

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Knockdown ofAKT3(PKBγ) andPI3KCASuppresses Cell Viability and Proliferation and Induces the Apoptosis of Glioblastoma Multiforme T98G Cells

BioMed Research International ◽

10.1155/2014/768181 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 13

Author(s):

Monika Paul-Samojedny ◽

Renata Suchanek ◽

Paulina Borkowska ◽

Adam Pudełko ◽

Aleksander Owczarek ◽

...

Keyword(s):

Glioblastoma Multiforme ◽

Cell Viability ◽

Poor Prognosis ◽

Therapeutic Strategy ◽

Inhibitory Effect ◽

Therapeutic Strategies ◽

Human Brain Tumor ◽

Qrt Pcr ◽

Wide Range ◽

Human Gbm

Glioblastoma multiforme (GBM) is the most malignant and invasive human brain tumor that is difficult to treat and has a very poor prognosis. Thus, new therapeutic strategies that target GBM are urgently needed. The PI3K/AKT/PTEN signaling pathway is frequently deregulated in a wide range of cancers. The present study was designed to examine the inhibitory effect ofAKT3orPI3KCAsiRNAs on GBM cell growth, viability, and proliferation.T98G cells were transfected withAKT3and/orPI3KCAsiRNAs. AKT3 and PI3KCA protein-positive cells were identified using FC and Western blotting. The influence of specific siRNAs on T98G cell viability, proliferation, cell cycle, and apoptosis was evaluated as well using FC. Alterations in the mRNA expression ofAKT3,PI3KCA, and apoptosis-related genes were analyzed using QRT-PCR. Knockdown ofAKT3and/orPI3KCAgenes in T98G cells led to a significant reduction in cell viability, the accumulation of subG1-phase cells and, a reduced fraction of cells in the S and G2/M phases. Additionally, statistically significant differences in the BAX/BCL-2 ratio and an increased percentage of apoptotic cells were found. The siRNA-inducedAKT3andPI3KCAmRNA knockdown may offer a novel therapeutic strategy to control the growth of human GBM cells.

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Two Genetic Loci Produce Distinct Carbohydrate-Rich Structural Components of the Pseudomonas aeruginosa Biofilm Matrix

Journal of Bacteriology ◽

10.1128/jb.186.14.4457-4465.2004 ◽

2004 ◽

Vol 186 (14) ◽

pp. 4457-4465 ◽

Cited By ~ 326

Author(s):

Lisa Friedman ◽

Roberto Kolter

Keyword(s):

Pseudomonas Aeruginosa ◽

Gene Cluster ◽

Biofilm Formation ◽

Genetic Locus ◽

Matrix Material ◽

Structural Components ◽

Matrix Component ◽

Cellular Aggregates ◽

Biofilm Matrix

ABSTRACT Pseudomonas aeruginosa forms biofilms, which are cellular aggregates encased in an extracellular matrix. Molecular genetics studies of three common autoaggregative phenotypes, namely wrinkled colonies, pellicles, and solid-surface-associated biofilms, led to the identification of two loci, pel and psl, that are involved in the production of carbohydrate-rich components of the biofilm matrix. The pel gene cluster is involved in the production of a glucose-rich matrix material in P. aeruginosa strain PA14 (L. Friedman and R. Kolter, Mol. Microbiol. 51:675-690, 2004). Here we investigate the role of the pel gene cluster in P. aeruginosa strain ZK2870 and identify a second genetic locus, termed psl, involved in the production of a mannose-rich matrix material. The 11 predicted protein products of the psl genes are homologous to proteins involved in carbohydrate processing. P. aeruginosa is thus able to produce two distinct carbohydrate-rich matrix materials. Either carbohydrate-rich matrix component appears to be sufficient for mature biofilm formation, and at least one of them is required for mature biofilm formation in P. aeruginosa strains PA14 and ZK2870.

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Strategies for the identification of novel inhibitors of deubiquitinating enzymes

Biochemical Society Transactions ◽

10.1042/bst0360828 ◽

2008 ◽

Vol 36 (5) ◽

pp. 828-832 ◽

Cited By ~ 27

Author(s):

Seth J. Goldenberg ◽

Jeffrey L. McDermott ◽

Tauseef R. Butt ◽

Michael R. Mattern ◽

Benjamin Nicholson

Keyword(s):

Therapeutic Strategy ◽

Ubiquitin Proteasome System ◽

Deubiquitinating Enzymes ◽

Protein Conjugates ◽

Advantages And Disadvantages ◽

Wide Range ◽

Ubiquitin Proteasome ◽

Effective Therapeutic Strategy ◽

Interferon Stimulated Gene 15 ◽

Review Current

Dysregulation of the UPS (ubiquitin–proteasome system) has been implicated in a wide range of pathologies including cancer, neurodegeneration and viral infection. Inhibiting the proteasome has been shown to be an effective therapeutic strategy in humans; yet toxicity with this target remains high. DUBs (deubiquitinating enzymes) represent an alternative target in the UPS with low predicted toxicity. Currently, there are no DUB inhibitors that have been used clinically. To address this situation, Progenra has developed a novel assay to measure the proteolytic cleavage of Ub (ubiquitin) or UBL (Ub-like protein) conjugates such as SUMO (small Ub-related modifier), NEDD8 (neural-precursor-cell-expressed, developmentally down-regulated 8) or ISG15 (interferon-stimulated gene 15) by isopeptidases. In this review, current platforms for detecting DUB inhibitors are discussed and the advantages and disadvantages of the approaches are underlined.

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Strategies and Approaches for Discovery of Small Molecule Disruptors of Biofilm Physiology

Molecules ◽

10.3390/molecules26154582 ◽

2021 ◽

Vol 26 (15) ◽

pp. 4582

Author(s):

Michael A. Trebino ◽

Rahul D. Shingare ◽

John B. MacMillan ◽

Fitnat H. Yildiz

Keyword(s):

Nucleic Acids ◽

Human Health ◽

Small Molecule ◽

Biofilm Formation ◽

Significant Risk ◽

Inhibition Mechanism ◽

Inhibitor Activity ◽

Structure Activity ◽

Wide Range ◽

Biofilm Matrix

Biofilms, the predominant growth mode of microorganisms, pose a significant risk to human health. The protective biofilm matrix, typically composed of exopolysaccharides, proteins, nucleic acids, and lipids, combined with biofilm-grown bacteria’s heterogenous physiology, leads to enhanced fitness and tolerance to traditional methods for treatment. There is a need to identify biofilm inhibitors using diverse approaches and targeting different stages of biofilm formation. This review discusses discovery strategies that successfully identified a wide range of inhibitors and the processes used to characterize their inhibition mechanism and further improvement. Additionally, we examine the structure–activity relationship (SAR) for some of these inhibitors to optimize inhibitor activity.

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Combinatorial Inhibition of mTORC2 and Hsp90 Leads to a Distinctly Effective Therapeutic Strategy in Malignant Pheochromocytoma

Current Cancer Drug Targets ◽

10.2174/1568009619666190206120615 ◽

2019 ◽

Vol 19 (9) ◽

pp. 698-706

Author(s):

Xiaohua Zhang ◽

Fengbin Gao ◽

Shan Zhong

Keyword(s):

Pc12 Cells ◽

Therapeutic Strategy ◽

Akt Signaling ◽

Therapeutic Strategies ◽

Malignant Pheochromocytoma ◽

Inhibit Tumor Growth ◽

Effective Therapeutic Strategy ◽

Hsp90 Function

Background: Malignant pheochromocytoma (mPCC) is an uncommon tumor with poor prognosis, and no effective therapeutic strategy exists as yet. Discovering new and effective therapeutic strategies to improve prognosis is an urgent need. Objective: To investigate whether a combinatorial inhibition of both mTORC2 and Hsp90 in PC12 cells could lead to a distinct anti-tumor effect in vitro and in vivo that was greater than the inhibition of mTORC2 or Hsp90 alone. Methods: Targeting mTORC2 was assessed by knockdown of Rictor using shRNA, and 17-AAG was used to inhibit Hsp90 function. Results: Combinatorial inhibition of both mTORC2 and Hsp90 could lead to a distinct anti-tumor effect in vitro that was greater than the inhibition of mTORC2 or Hsp90 alone. Inhibiting Hsp90 specifically could inhibit tumor growth of sh-Rictor cells in vivo, suggesting that the combinatorial inhibition of both mTORC2 and Hsp90 could lead to a distinct anti-tumor effect in vivo. Western blotting has shown that both p-Akt Ser473 and p-Akt Thr450 showed significantly decreased expression after targeting mTORC2, while p-Akt Thr308 did not. However, all three different p-AKTs, including p-Akt Ser473, p-Akt Thr450 and p-Akt Thr308, showed a significantly decreased expression in combinatorial inhibition of both mTORC2 and Hsp90. Collectively, it revealed that combinatorial inhibition of mTORC2 and Hsp90 could destabilize the Akt signaling. Conclusion: Our results demonstrated that combinatorial inhibition of mTORC2 and Hsp90 could increase their anti-tumor effect and destabilize the Akt signaling in PC12 cells, suggesting a combinatorial inhibition of both mTORC2 and Hsp90 which might be an effective therapeutic strategy for mPCC.

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Molecular underpinnings of enzalutamide resistance

Endocrine Related Cancer ◽

10.1530/erc-17-0136 ◽

2018 ◽

Vol 25 (11) ◽

pp. R545-R557 ◽

Cited By ~ 9

Author(s):

S Prekovic ◽

T Van den Broeck ◽

S Linder ◽

M E van Royen ◽

A B Houtsmuller ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Clinical Research ◽

Survival Time ◽

Therapeutic Strategy ◽

Therapeutic Strategies ◽

Effective Therapeutic Strategy ◽

Novel Therapeutic Strategies ◽

Improvement In Survival ◽

Novel Therapeutic

Prostate cancer (PCa) is among the most common adult malignancies, and the second leading cause of cancer-related death in men. As PCa is hormone dependent, blockade of the androgen receptor (AR) signaling is an effective therapeutic strategy for men with advanced metastatic disease. The discovery of enzalutamide, a compound that effectively blocks the AR axis and its clinical application has led to a significant improvement in survival time. However, the effect of enzalutamide is not permanent, and resistance to treatment ultimately leads to development of lethal disease, for which there currently is no cure. This review will focus on the molecular underpinnings of enzalutamide resistance, bridging the gap between the preclinical and clinical research on novel therapeutic strategies for combating this lethal stage of prostate cancer.

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Pharmaceutical Co-Crystals - Design, Development and Applications

Drug Delivery Letters ◽

10.2174/2210303109666191211145144 ◽

2020 ◽

Vol 10 (3) ◽

pp. 169-184

Author(s):

Rachna Anand ◽

Arun Kumar ◽

Arun Nanda

Keyword(s):

Physicochemical Properties ◽

Crystal Engineering ◽

Pharmacological Action ◽

Physicochemical Characteristics ◽

Research Area ◽

Dissolution Profile ◽

Design Development ◽

Drug Molecule ◽

Wide Range ◽

Major Factors

Background: Solubility and dissolution profile are the major factors which directly affect the biological activity of a drug and these factors are governed by the physicochemical properties of the drug. Crystal engineering is a newer and promising approach to improve physicochemical characteristics of a drug without any change in its pharmacological action through a selection of a wide range of easily available crystal formers. Objective: The goal of this review is to summarize the importance of crystal engineering in improving the physicochemical properties of a drug, methods of design, development, and applications of cocrystals along with future trends in research of pharmaceutical co-crystals. Co-crystallization can also be carried out for the molecules which lack ionizable functional groups, unlike salts which require ionizable groups. Conclusion: Co-crystals is an interesting and promising research area amongst pharmaceutical scientists to fine-tune the physicochemical properties of drug materials. Co-crystallization can be a tool to increase the lifecycle of an older drug molecule. Crystal engineering carries the potential of being an advantageous technique than any other approach used in the pharmaceutical industry. Crystal engineering offers a plethora of biopharmaceutical and physicochemical enhancements to a drug molecule without the need of any pharmacological change in the drug.

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An Overview on the Rheology, Mechanical Properties, Durability, 3D Printing, and Microstructural Performance of Nanomaterials in Cementitious Composites

Materials ◽

10.3390/ma14112950 ◽

2021 ◽

Vol 14 (11) ◽

pp. 2950

Author(s):

Hongwei Song ◽

Xinle Li

Keyword(s):

Mechanical Properties ◽

3D Printing ◽

Three Dimensional ◽

Cementitious Materials ◽

Research Area ◽

Cementitious Composites ◽

Split Tensile Strength ◽

Contour Crafting ◽

Wide Range ◽

Active Research

The most active research area is nanotechnology in cementitious composites, which has a wide range of applications and has achieved popularity over the last three decades. Nanoparticles (NPs) have emerged as possible materials to be used in the field of civil engineering. Previous research has concentrated on evaluating the effect of different NPs in cementitious materials to alter material characteristics. In order to provide a broad understanding of how nanomaterials (NMs) can be used, this paper critically evaluates previous research on the influence of rheology, mechanical properties, durability, 3D printing, and microstructural performance on cementitious materials. The flow properties of fresh cementitious composites can be measured using rheology and slump. Mechanical properties such as compressive, flexural, and split tensile strength reveal hardened properties. The necessary tests for determining a NM’s durability in concrete are shrinkage, pore structure and porosity, and permeability. The advent of modern 3D printing technologies is suitable for structural printing, such as contour crafting and binder jetting. Three-dimensional (3D) printing has opened up new avenues for the building and construction industry to become more digital. Regardless of the material science, a range of problems must be tackled, including developing smart cementitious composites suitable for 3D structural printing. According to the scanning electron microscopy results, the addition of NMs to cementitious materials results in a denser and improved microstructure with more hydration products. This paper provides valuable information and details about the rheology, mechanical properties, durability, 3D printing, and microstructural performance of cementitious materials with NMs and encourages further research.

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