Ångstrom‐Scale Silver Particles as a Promising Agent for Low‐Toxicity Broad‐Spectrum Potent Anticancer Therapy

2019 ◽  
Vol 29 (23) ◽  
pp. 1808556 ◽  
Author(s):  
Zhen‐Xing Wang ◽  
Chun‐Yuan Chen ◽  
Yang Wang ◽  
Fu‐Xing‐Zi Li ◽  
Jie Huang ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Anticancer Therapy ◽  
Silver Particles ◽  
Promising Agent ◽  
Low Toxicity

scholarly journals Non-Toxic Virucidal Macromolecules Show High Efficacy Against Influenza Virus Ex Vivo and In Vivo

2020 ◽  
Author(s):  
Ozgun Kocabiyik ◽  
Valeria Cagno ◽  
Paulo Jacob Silva ◽  
Yong Zhu ◽  
Laura Sedano ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Viral Infections ◽  
Ex Vivo ◽  
Public Health Problem ◽  
Major Public Health Problem ◽  
New Class ◽  
Influenza Strain ◽  
Low Toxicity

AbstractInfluenza is one of the most widespread viral infections worldwide and represents a major public health problem. The risk that one of the next pandemics is caused by an influenza strain is very high. It is very important to develop broad-spectrum influenza antivirals to be ready for any possible vaccine shortcomings. Anti-influenza drugs are available but they are far from ideal. Arguably, an ideal antiviral should target conserved viral domains and be virucidal, i.e. irreversibly inhibit viral infectivity. Here, we describe a new class of broad-spectrum anti-influenza macromolecules that meets these criteria and displays exceedingly low toxicity. These compounds are based on a cyclodextrin core modified on its primary face with long hydrophobic linkers terminated in 6’sialyl-N-acetyllactosamine (6’SLN) or 3’SLN. SLN enables nanomolar inhibition of the viruses while the hydrophobic linkers confer irreversibility to the inhibition. The combination of these two properties allows for efficacy in vitro against several human or avian influenza strains, as well as against a 2009 pandemic influenza strain ex vivo. Importantly, we show that, in mice, the compounds provide therapeutic efficacy when administered 24h post-infection allowing 90% survival as opposed to no survival for the placebo and oseltamivir..

scholarly journals Poly-Gamma-Glutamic Acid (γ-PGA)-Based Encapsulation of Adenovirus to Evade Neutralizing Antibodies

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2565 ◽  
Author(s):  
Ibrahim Khalil ◽  
Martin Khechara ◽  
Sathishkumar Kurusamy ◽  
Angel Armesilla ◽  
Abhishek Gupta ◽  
...  
Keyword(s):  
Glutamic Acid ◽  
Neutralizing Antibodies ◽  
Viral Vectors ◽  
Viral Vector ◽  
Neutralizing Antibody ◽  
Anticancer Therapy ◽  
Significant Research ◽  
Low Toxicity ◽  
Cancerous Cells

In recent years, there has been an increasing interest in oncolytic adenoviral vectors as an alternative anticancer therapy. The induction of an immune response can be considered as a major limitation of this kind of application. Significant research efforts have been focused on the development of biodegradable polymer poly-gamma-glutamic acid (γ-PGA)-based nanoparticles used as a vector for effective and safe anticancer therapy, owing to their controlled and sustained-release properties, low toxicity, as well as biocompatibility with tissue and cells. This study aimed to introduce a specific destructive and antibody blind polymer-coated viral vector into cancer cells using γ-PGA and chitosan (CH). Adenovirus was successfully encapsulated into the biopolymer particles with an encapsulation efficiency of 92% and particle size of 485 nm using the ionic gelation method. Therapeutic agents or nanoparticles (NPs) that carry therapeutics can be directed specifically to cancerous cells by decorating their surfaces using targeting ligands. Moreover, in vitro neutralizing antibody response against viral capsid proteins can be somewhat reduced by encapsulating adenovirus into γ-PGA-CH NPs, as only 3.1% of the encapsulated adenovirus was detected by anti-adenovirus antibodies in the presented work compared to naked adenoviruses. The results obtained and the unique characteristics of the polymer established in this research could provide a reference for the coating and controlled release of viral vectors used in anticancer therapy.

scholarly journals Metallo-β-Lactamase Inhibitors Inspired on Snapshots from the Catalytic Mechanism

Biomolecules ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 854 ◽  
Author(s):  
Antonela R. Palacios ◽  
María-Agustina Rossi ◽  
Graciela S. Mahler ◽  
Alejandro J. Vila
Keyword(s):  
Transition State ◽  
Broad Spectrum ◽  
Catalytic Mechanism ◽  
Structural Diversity ◽  
Resistance Mechanisms ◽  
Amide Bond ◽  
Similar Reaction ◽  
Hydrolysis Process ◽  
Common Strategy ◽  
Low Toxicity

β-Lactam antibiotics are the most widely prescribed antibacterial drugs due to their low toxicity and broad spectrum. Their action is counteracted by different resistance mechanisms developed by bacteria. Among them, the most common strategy is the expression of β-lactamases, enzymes that hydrolyze the amide bond present in all β-lactam compounds. There are several inhibitors against serine-β-lactamases (SBLs). Metallo-β-lactamases (MBLs) are Zn(II)-dependent enzymes able to hydrolyze most β-lactam antibiotics, and no clinically useful inhibitors against them have yet been approved. Despite their large structural diversity, MBLs have a common catalytic mechanism with similar reaction species. Here, we describe a number of MBL inhibitors that mimic different species formed during the hydrolysis process: substrate, transition state, intermediate, or product. Recent advances in the development of boron-based and thiol-based inhibitors are discussed in the light of the mechanism of MBLs. We also discuss the use of chelators as a possible strategy, since Zn(II) ions are essential for substrate binding and catalysis.

scholarly journals Broad Spectrum Antiviral Properties of Cardiotonic Steroids Used as Potential Therapeutics for Emerging Coronavirus Infections

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1839
Author(s):  
Young-Hee Jin ◽  
Sangeun Jeon ◽  
Jihye Lee ◽  
Seungtaek Kim ◽  
Min Seong Jang ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Expression Patterns ◽  
Intraperitoneal Administration ◽  
Antiviral Drug ◽  
Pharmacokinetic Studies ◽  
Repeated Dose Toxicity ◽  
Infected Cells ◽  
Cyp Inhibition ◽  
Low Toxicity ◽  
Coronavirus Infections

Cardiotonic steroids are steroid-like natural compounds known to inhibit Na+/K+-ATPase pumps. To develop a broad-spectrum antiviral drug against the emerging coronavirus infection, this study assessed the antiviral properties of these compounds. The activity of seven types of cardiotonic steroids against the MERS-CoV, SARS-CoV, and SARS-CoV-2 coronavirus varieties was analyzed using immunofluorescence antiviral assay in virus-infected cells. Bufalin, cinobufagin, and telocinobufagin showed high anti-MERS-CoV activities (IC50, 0.017~0.027 μM); bufalin showed the most potent anti-SARS-CoV and SARS-CoV-2 activity (IC50, 0.016~0.019 μM); cinobufotalin and resibufogenin showed comparatively low anti-coronavirus activity (IC50, 0.231~1.612 μM). Differentially expressed genes in Calu3 cells treated with cinobufagin, telocinobufagin, or bufalin, which had high antiviral activity during MERS-CoV infection were analyzed using QuantSeq 3′ mRNA-Seq analysis and data showed similar gene expression patterns. Furthermore, the intraperitoneal administration of 10 mg/kg/day bufalin, cinobufagin, or digitoxin induced 100% death after 1, 2, and 4 days in 5-day repeated dose toxicity studies and it indicated that bufalin had the strongest toxicity. Pharmacokinetic studies suggested that telocinobufagin, which had high anti-coronavirus activity and low toxicity, had better microsomal stability, lower CYP inhibition, and better oral bioavailability than cinobufagin. Therefore, telocinobufagin might be the most promising cardiotonic steroid as a therapeutic for emerging coronavirus infections, including COVID-19.

scholarly journals Bioevaluation of Ranatuerin-2Pb from the Frog Skin Secretion of Rana pipiens and its Truncated Analogues

Biomolecules ◽  
2019 ◽  
Vol 9 (6) ◽  
pp. 249 ◽  
Author(s):  
Zhou ◽  
Shi ◽  
Zhong ◽  
Ye ◽  
Ma ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Broad Spectrum ◽  
Rana Pipiens ◽  
Galleria Mellonella ◽  
Skin Secretion ◽  
Bacterial Killing ◽  
Structure Activity ◽  
Promising Agent ◽  
Large Numbers ◽  
Relationship Of

Antimicrobial peptides (AMPs) are considered as a promising agent to overcome the drug-resistance of bacteria. Large numbers of AMPs have been identified from the skin secretion of Rana pipiens, including brevinins, ranatuerins, temporins and esculentins. In this study, the cDNA precursor of a broad-spectrum antimicrobial peptide, ranatuerin-2Pb, was cloned and identified. Additionally, two truncated analogues, RPa and RPb, were synthesised to investigate the structure-activity relationship of ranatuerin-2Pb. RPa lost antimicrobial activity against Candida albicans, MRSA, Enterococcus faecalis and Pseudomonas aeruginosa, while RPb retained its broad-spectrum antimicrobial activity. Additionally, ranatuerin-2Pb, RPa and RPb demonstrated inhibition and eradication effects against Staphylococcus aureus biofilm. RPb showed a rapid bacterial killing manner via membrane permeabilization without damaging the cell membrane of erythrocytes. Moreover, RPb decreased the mortality of S. aureus infected Galleria mellonella larvae. Collectively, our results suggested that RPb may pave a novel way for natural antimicrobial drug design.

scholarly journals Preclinical Evaluation of Acylhydrazone SB-AF-1002 as a Novel Broad-Spectrum Antifungal Agent

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Cristina Lazzarini ◽  
Krupanandan Haranahalli ◽  
J. Brian McCarthy ◽  
John Mallamo ◽  
Iwao Ojima ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Mammalian Cells ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Parent Compound ◽  
Invasive Fungal Infections ◽  
Current Standard ◽  
New Class ◽  
Low Toxicity

ABSTRACT The incidence of invasive fungal infections is rising due to the increase in susceptible populations. Current clinically available drugs have therapeutic limitations due to toxicity, a narrow spectrum of activity, and, more importantly, the consistent rise of fungal species that are intrinsically resistant or that develop resistance due to prolonged therapy. Thus, there is an urgent need for new broad-spectrum antifungal agents with low toxicity and a novel mechanism of action. We previously reported a new class of potent antifungal compounds, acylhydrazones, that target the fungal sphingolipid pathway. Based upon our initial lead molecules, (E)-N′-(5-bromo-2-hydroxybenzylidene)-2-methylbenzohydrazide and D13, we performed a structure-activity relationship study, synthesizing ca. 300 new compounds. Of these, 5 compounds were identified to be the most promising for further studies, based on their broad-spectrum activity and low toxicity in mammalian cells lines. Among these top 5 lead compounds, we report here the impressive in vivo activity of 2,4-dibromo-N′-(5-bromo-2-hydroxybenzylidene)benzohydrazide (SB-AF-1002) in several models of systemic fungal infection. Our data show that SB-AF-1002 is efficacious and outperforms current standard-of-care drugs in models of invasive fungal infections, such as cryptococcosis, candidiasis, and aspergillosis. Specifically, animals treated with SB-AF-1002 not only survived the infection but also showed a clearing of fungal cells from key organs. Moreover, SB-AF-1002 was very effective in an aspergillosis model as a prophylactic therapy. SB-AF-1002 also displayed acceptable pharmacokinetic properties in mice, similar to those of the parent compound, D13. These results clearly indicate that our novel acylhydrazones constitute a new class of highly potent and efficacious antifungal agents which warrant further development for the treatment of invasive fungal infections.

scholarly journals 1,2,4-Oxadiazole-Based Bio-Isosteres of Benzamides: Synthesis, Biological Activity and Toxicity to Zebrafish Embryo

2021 ◽  
Vol 22 (5) ◽  
pp. 2367
Author(s):  
Sen Yang ◽  
Chao-Li Ren ◽  
Tian-Yang Ma ◽  
Wen-Qian Zou ◽  
Li Dai ◽  
...  
Keyword(s):  
Biological Activity ◽  
Antifungal Activity ◽  
Acute Toxicity ◽  
High Activity ◽  
Broad Spectrum ◽  
Zebrafish Embryo ◽  
Thanatephorus Cucumeris ◽  
Low Toxicity ◽  
New Compounds ◽  
Better Than

To discover new compounds with broad spectrum and high activity, we designed a series of novel benzamides containing 1,2,4-oxadiazole moiety by bioisosterism, and 28 benzamides derivatives with antifungal activity were synthesized. These compounds were evaluated against four fungi: Botrytis cinereal, FusaHum graminearum, Marssonina mali, and Thanatephorus cucumeris. The results indicated that most of the compounds displayed good fungicidal activities, especially against Botrytis cinereal. For example, 10a (84.4%), 10d (83.6%), 10e (83.3%), 10f (83.1%), 10i (83.3%), and 10l (83.6%) were better than pyraclostrobin (81.4%) at 100 mg/L. In addition, the acute toxicity of 10f to zebrafish embryo was 20.58 mg/L, which was classified as a low-toxicity compound.

scholarly journals Peptide-Mediated Liposomal Drug Delivery System Targeting Tumor Blood Vessels in Anticancer Therapy

2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
Han-Chung Wu ◽  
De-Kuan Chang
Keyword(s):  
Drug Delivery ◽  
Endothelial Cells ◽  
Blood Vessels ◽  
Antiangiogenic Therapy ◽  
Anticancer Therapy ◽  
Liposomal Drug ◽  
Surface Receptors ◽  
Low Toxicity ◽  
Tumor Blood Vessels ◽  
Potential Methods

Solid tumors are known to recruit new blood vessels to support their growth. Therefore, unique molecules expressed on tumor endothelial cells can function as targets for the antiangiogenic therapy of cancer. Current efforts are focusing on developing therapeutic agents capable of specifically targeting cancer cells and tumor-associated microenvironments including tumor blood vessels. These therapies hold the promise of high efficacy and low toxicity. One recognized strategy for improving the therapeutic effectiveness of conventional chemotherapeutics is to encapsulate anticancer drugs into targeting liposomes that bind to the cell surface receptors expressed on tumor-associated endothelial cells. These anti-angiogenic drug delivery systems could be used to target both tumor blood vessels as well as the tumor cells, themselves. This article reviews the mechanisms and advantages of various present and potential methods using peptide-conjugated liposomes to specifically destroy tumor blood vessels in anticancer therapy.

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