scholarly journals Understanding the Genetics of Viral Drug Resistance by Integrating Clinical Data and Mining of the Scientific Literature

2021 ◽  
Author(s):  
An Goto ◽  
Raul Rodriguez-Esteban ◽  
Sebastian H. Scharf ◽  
Garrett M. Morris
Keyword(s):  
Drug Resistance ◽  
Clinical Data ◽  
Disulfide Bonds ◽  
Scientific Literature ◽  
Binding Pocket ◽  
New Drugs ◽  
Viral Diseases ◽  
Emerging Viruses ◽  
Hbv Genotype ◽  
Mutational Hotspots

Drug resistance caused by mutations is a public health threat for existing and emerging viral diseases. A wealth of evidence about these mutations and their clinically-associated phenotypes is scattered across the literature, but a comprehensive perspective is usually lacking. This work aimed to produce a clinically-relevant view for the case of Hepatitis B virus (HBV) mutations by combining a chronic HBV clinical study with a compendium of genetic mutations systematically gathered from the scientific literature. We enriched clinical mutation data by systematically mining 2,472,725 scientific articles from PubMed Central in order to gather information about the HBV mutational landscape. By performing this analysis, we were able to identify mutational hotspots for each HBV genotype (A-E) and gene (C, X, P, S), as well as the location of disulfide bonds associated with these mutations. Through a modelling study, we also identified a mutational position common in both the clinical data and the literature that is located at the binding pocket for a known anti-HBV drug, namely entecavir. The results of this novel approach shows the potential of integrated analyses to assist in the development of new drugs for viral diseases that are more robust to resistance. Such analyses should be of particular interest due to the increasing importance of viral resistance in established and emerging viruses, such as for newly-developed drugs against SARS-CoV-2.

Pharmacological Targeting of Neuronal Kv7.2/3 Channels: A Focus on Chemotypes and Receptor Sites

2018 ◽  
Vol 25 (23) ◽  
pp. 2637-2660 ◽  
Author(s):  
Francesco Miceli ◽  
Maria V. Soldovieri ◽  
Paolo Ambrosino ◽  
Laura Manocchio ◽  
Ilaria Mosca ◽  
...  
Keyword(s):  
Metabolic Diseases ◽  
Scientific Literature ◽  
New Drugs ◽  
Current Status ◽  
Functional Heterogeneity ◽  
Molecular Scaffolds ◽  
Kv7 Channels ◽  
Receptor Sites ◽  
Pharmacological Targets ◽  
Pharmacological Potential

Background: The Kv7 (KCNQ) subfamily of voltage-gated potassium channels consists of 5 members (Kv7.1-5) each showing characteristic tissue distribution and physiological roles. Given their functional heterogeneity, Kv7 channels represent important pharmacological targets for the development of new drugs for neuronal, cardiovascular and metabolic diseases. <p> Objective: In the present manuscript, we focus on describing the pharmacological relevance and potential therapeutic applications of drugs acting on neuronally-expressed Kv7.2/3 channels, placing particular emphasis on the different chemotypes, and highlighting their pharmacodynamic and, whenever possible, pharmacokinetic peculiarities. <p> Methods: The present work is based on an in-depth search of the currently available scientific literature, and on our own experience and knowledge in the field of neuronal Kv7 channel pharmacology. Space limitations impeded to describe the full pharmacological potential of Kv7 channels; thus, we have chosen to focus on neuronal channels composed of Kv7.2 and Kv7.3 subunits, and to mainly concentrate on their involvement in epilepsy. <p> Results: An astonishing heterogeneity in the molecular scaffolds exploitable to develop Kv7.2/3 modulators is evident, with important structural/functional peculiarities of distinct compound classes. <p> Conclusion: In the present work we have attempted to show the current status and growing potential of the Kv7 pharmacology field. We anticipate a bright future for the field, and express our hopes that the efforts herein reviewed will result in an improved treatment of hyperexcitability (or any other) diseases.

Recent Advances in the Synthesis and Development of Nitroaromatics as Anti-Infective Drugs

2020 ◽  
Vol 26 (36) ◽  
pp. 4658-4674 ◽  
Author(s):  
Christina Kannigadu ◽  
David. D. N'Da
Keyword(s):  
Infectious Disease ◽  
Drug Resistance ◽  
Chest Pain ◽  
Muscle Pain ◽  
New Drugs ◽  
Lymph Glands ◽  
Recent Advances ◽  
Personality Changes ◽  
Clinical Drugs ◽  
Antiparasitic Agents

: Infectious diseases commonly occur in tropical and sub-tropical countries. The pathogens of such diseases are able to multiply in human hosts, warranting their continual survival. Infections that are commonplace include malaria, chagas, trypanosomiasis, giardiasis, amoebiasis, toxoplasmosis and leishmaniasis. Malaria is known to cause symptoms, such as high fever, chills, nausea and vomiting, whereas chagas disease causes enlarged lymph glands, muscle pain, swelling and chest pain. People suffering from African trypanosomiasis may experience severe headaches, irritability, extreme fatigue and swollen lymph nodes. As an infectious disease progresses, the human host may also experience personality changes and neurologic problems. If left untreated, most of these diseases can lead to death. : Parasites, microbes and bacteria are increasingly adapting and generating strains that are resistant to current clinical drugs. Drug resistance creates an urgency for the development of new drugs to treat these infections. Nitro containing drugs, such as chloramphenicol, metronidazole, tinidazole and secnidazole had been banned for use as antiparasitic agents due to their toxicity. However, recent discoveries of nitrocontaining anti-tuberculosis drugs, i.e. delamanid and pretonamid, and the repurposing of flexinidazole for use in combination with eflornithine for the treatment of human trypanosomiasis, have ignited interest in nitroaromatic scaffolds as viable sources of potential anti-infective agents. : This review highlights the differences between old and new nitration methodologies. It furthermore offers insights into recent advances in the development of nitroaromatics as anti-infective drugs.

Mycobacterial DNA Replication as a Target for Antituberculosis Drug Discovery

2017 ◽  
Vol 17 (19) ◽  
pp. 2129-2142 ◽  
Author(s):  
Renata Płocinska ◽  
Malgorzata Korycka-Machala ◽  
Przemyslaw Plocinski ◽  
Jaroslaw Dziadek
Keyword(s):  
Drug Resistance ◽  
Dna Replication ◽  
Drug Targets ◽  
Rapid Development ◽  
New Drugs ◽  
Drug Resistant ◽  
Antituberculosis Drug ◽  
Nucleotide Synthesis ◽  
Antituberculosis Therapy ◽  
Optimal Drug

Background: Mycobacterium tuberculosis (M. tuberculosis), the causative agent of tuberculosis, is a leading infectious disease organism, causing millions of deaths each year. This serious pathogen has been greatly spread worldwide and recent years have observed an increase in the number of multi-drug resistant and totally drug resistant M. tuberculosis strains (WHO report, 2014). The danger of tuberculosis becoming an incurable disease has emphasized the need for the discovery of a new generation of antimicrobial agents. The development of novel alternative medical strategies, new drugs and the search for optimal drug targets are top priority areas of tuberculosis research. Factors: Key characteristics of mycobacteria include: slow growth, the ability to transform into a metabolically silent - latent state, intrinsic drug resistance and the relatively rapid development of acquired drug resistance. These factors make finding an ideal antituberculosis drug enormously challenging, even if it is designed to treat drug sensitive tuberculosis strains. A vast majority of canonical antibiotics including antituberculosis agents target bacterial cell wall biosynthesis or DNA/RNA processing. Novel therapeutic approaches are being tested to target mycobacterial cell division, twocomponent regulatory factors, lipid synthesis and the transition between the latent and actively growing states. Discussion and Conclusion: This review discusses the choice of cellular targets for an antituberculosis therapy, describes putative drug targets evaluated in the recent literature and summarizes potential candidates under clinical and pre-clinical development. We focus on the key cellular process of DNA replication, as a prominent target for future antituberculosis therapy. We describe two main pathways: the biosynthesis of nucleic acids precursors – the nucleotides, and the synthesis of DNA molecules. We summarize data regarding replication associated proteins that are critical for nucleotide synthesis, initiation, unwinding and elongation of the DNA during the replication process. They are pivotal processes required for successful multiplication of the bacterial cells and hence they are extensively investigated for the development of antituberculosis drugs. Finally, we summarize the most potent inhibitors of DNA synthesis and provide an up to date report on their status in the clinical trials.

scholarly journals pH-activated, mitochondria-targeted, and redox-responsive delivery of paclitaxel nanomicelles to overcome drug resistance and suppress metastasis in lung cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
He Wang ◽  
Wenwen Shi ◽  
Danning Zeng ◽  
Qiudi Huang ◽  
Jiacui Xie ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Disulfide Bonds ◽  
Cancer Metastasis ◽  
Mitochondrial Outer Membrane ◽  
Drug Resistant ◽  
Redox Responsive ◽  
Dimethylmaleic Anhydride ◽  
Extended Circulation ◽  
Mitochondria Targeting

Abstract Background Mitochondria play a role in the occurrence, development, drug resistance, metastasis, and other functions of cancer and thus are a drug target. An acid-activated mitochondria-targeting drug nanocarrier with redox-responsive function was constructed in the present study. However, whether this vector can precisely delivery paclitaxel (PTX) to enhance therapeutic efficacy in drug-resistant lung cancer is unknown. Results Acid-cleavable dimethylmaleic anhydride (DA) was used to modify pluronic P85-conjugated mitochondria-targeting triphenylphosphonium (TPP) using disulfide bonds as intermediate linkers (DA-P85-SS-TPP and DA-P-SS-T). The constructed nanocarriers demonstrated enhanced cellular uptake and selective mitochondrial targeting at extracellular pH characteristic for a tumor (6.5) and were characterized by extended circulation in the blood. TPP promoted the targeting of the DA-P-SS-T/PTX nanomicelles to the mitochondrial outer membrane to decrease the membrane potential and ATP level, resulting in inhibition of P-glycoprotein and suppression of drug resistance and cancer metastasis. PTX was also rapidly released in the presence of high glutathione (GSH) levels and directly diffused into the mitochondria, resulting in apoptosis of drug-resistant lung cancer cells. Conclusions These promising results indicated that acid-activated mitochondria-targeting and redox-responsive nanomicelles potentially represent a significant advancement in cancer treatment. Graphic Abstarct

scholarly journals Identification and Characterization of Multiple Myeloma Stem Cell-Like Cells

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3523
Author(s):  
Wancheng Guo ◽  
Haiqin Wang ◽  
Peng Chen ◽  
Xiaokai Shen ◽  
Boxin Zhang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Stem Cell ◽  
New Drugs ◽  
Cell Therapies ◽  
High Relapse Rate ◽  
High Incidence ◽  
Poorly Differentiated ◽  
Identification And Characterization

Multiple myeloma (MM) is a B-cell tumor of the blood system with high incidence and poor prognosis. With a further understanding of the pathogenesis of MM and the bone marrow microenvironment, a variety of adjuvant cell therapies and new drugs have been developed. However, the drug resistance and high relapse rate of MM have not been fundamentally resolved. Studies have shown that, in patients with MM, there is a type of poorly differentiated progenitor cell (MM stem cell-like cells, MMSCs). Although there is no recognized standard for identification and classification, it is confirmed that they are closely related to the drug resistance and relapse of MM. This article therefore systematically summarizes the latest developments in MMSCs with possible markers of MMSCs, introduces the mechanism of how MMSCs work in MM resistance and recurrence, and discusses the active pathways that related to stemness of MM.

scholarly journals Emerging Viral Diseases of Tomato Crops

2010 ◽  
Vol 23 (5) ◽  
pp. 539-548 ◽  
Author(s):  
Inge M. Hanssen ◽  
Moshe Lapidot ◽  
Bart P. H. J. Thomma
Keyword(s):  
Crop Production ◽  
Production Systems ◽  
Genetic Resistance ◽  
International Travel ◽  
Viral Diseases ◽  
Limiting Factor ◽  
Emerging Viruses ◽  
Plant Materials ◽  
Tomato Production ◽  
Climate Conditions

Viral diseases are an important limiting factor in many crop production systems. Because antiviral products are not available, control strategies rely on genetic resistance or hygienic measures to prevent viral diseases, or on eradication of diseased crops to control such diseases. Increasing international travel and trade of plant materials enhances the risk of introducing new viruses and their vectors into production systems. In addition, changing climate conditions can contribute to a successful spread of newly introduced viruses or their vectors and establishment of these organisms in areas that were previously unfavorable. Tomato is economically the most important vegetable crop worldwide and many viruses infecting tomato have been described, while new viral diseases keep emerging. Pepino mosaic virus is a rapidly emerging virus which has established itself as one of the most important viral diseases in tomato production worldwide over recent years. Begomovirus species and other whitefly-transmitted viruses are invading into new areas, and several recently described new viruses such as Tomato torrado virus and new Tospovirus species are rapidly spreading over large geographic areas. In this article, emerging viruses of tomato crops are discussed.

Emerging viral diseases

2021 ◽  
Vol 1 (2) ◽  
pp. 020-027
Author(s):  
Angel San Miguel Hernández ◽  
María San Miguel Rodríguez ◽  
Angel San Miguel Rodriguez
Keyword(s):  
Geographic Distribution ◽  
Viral Infections ◽  
Viral Diseases ◽  
Social Changes ◽  
Emerging Viruses ◽  
Susceptible Population ◽  
Exponential Increase ◽  
Emerging Virus ◽  
Virus Model ◽  
Emerging Viral Diseases

Emerging viral diseases encompass two types, those of new appearance in the population and those that we previously knew about or re-emerging, but that at a certain moment present an exponential increase in incidence or geographic distribution in the form of epidemics or outbreaks. These emerging and re-emerging viruses share a series of characteristics that establish the emerging virus model, such as having an RNA genome, being zoonotic, transmitted by vectors and transmissible to humans, that the virus is able to recognize and provoke a response in receptors. Conserved in several species and inhabiting ecosystems that undergo ecological, demographic or social changes that favor the spread of the virus. There are different factors that contribute to facilitating the emergence of viral infections, although this is made up of three fundamental aspects such as the susceptible population, the virus itself and the environment where both can interact.

TREATMENT OF CARBAPENEM RESISTANT ENTEROBACTERIACEAE URINARY TRACT INFECTION WITH COMBINATION OF AMIKACIN AND MEROPENEM

2021 ◽  
pp. 54-55
Author(s):  
Jayesh Kalbhande ◽  
Vicky Kuldeep
Keyword(s):  
Drug Resistance ◽  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
New Drugs ◽  
Resistant Organism ◽  
Drug Resistant ◽  
Carbapenem Resistant ◽  
Multiple Drugs ◽  
Near Future

Drug resistance of bacteria is biggest challenge humanity is going to face in near future. Bacteria are rapidly developing resistant to multiple drugs and there are not many new drugs in pipeline. Infection because of drug resistant organism is a common cause of morbidity and mortality in intensive care unit. If acquisition of drug resistance by microorganism progresses at this rate, that time is not very far when we will be pushed in to preantibiotic era. We need to develop new strategies to combat drug resistant by microorganism. We report a case of highly drug resistant urinary tract infection caused by Klebsiella. This strain was resistant to both Inj. Meropenem and Inj. Amikacin. This case was successfully treated by combination of Inj. Meropenem and Inj. Amikacin and complete resolution of infection was observed.

IMB-BZ as an Inhibitor Targeting ESX-1 Secretion System to Control Mycobacterial Infection

2021 ◽  
Author(s):  
Pingping Jia ◽  
Yi Zhang ◽  
Jian Xu ◽  
Mei Zhu ◽  
Shize Peng ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterial Infection ◽  
Underlying Mechanism ◽  
Inhibitory Effect ◽  
New Drugs ◽  
Dependent Manner ◽  
High Potency ◽  
Resistance Development

Abstract Background Resistance to anti-tuberculosis (TB) drug is a major issue in TB control, and demands the discovery of new drugs targeting virulence factor ESX-1. Methods We first established a high-throughput screen (HTS) assay for the discovery of ESX-1 secretion inhibitors. The positive hits were then evaluated for the potency of diminishing the survival of virulent mycobacterium and reducing bacterial virulence. We further investigated the probability of inducing drug-resistance and the underlying mechanism using M-PFC. Results A robust HTS assay was developed to identify small molecules that inhibit ESX-1 secretion without impairing bacterial growth in vitro. A hit named IMB-BZ specifically inhibits the secretion of CFP-10 and reduces virulence in an ESX-1-dependent manner, therefore resulting in significant reduction in intracellular and in vivo survival of mycobacteria. Blocking the CFP-10-EccCb1 interaction directly or indirectly underlies the inhibitory effect of IMB-BZ on the secretion of CFP-10. Importantly, our finding shows that the ESX-1 inhibitors pose low risk of drug resistance development by mycobacteria in vitro as compared with traditional anti-TB drug, and exhibit high potency against chronic mycobacterial infection. Conclusion Targeting ESX-1 may lead to the development of novel therapeutics for tuberculosis. IMB-BZ holds the potential for future development into a new anti-TB drug.

Current Advances and Outlook in Gastric Cancer Chemoresistance: A Review

2021 ◽  
Vol 16 ◽  
Author(s):  
Sheng-Xiong Zhang ◽  
Wei Liu ◽  
Bo Ai ◽  
Ling-Ling Sun ◽  
Zhe-Sheng Chen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Drug Resistance ◽  
Natural Products ◽  
Chemotherapy Resistance ◽  
Underlying Mechanism ◽  
Primary Treatment ◽  
New Drugs ◽  
Cancer Drug ◽  
Cancer Drug Resistance ◽  
Cancer Pharmacology

Background: Surgical resection of the lesion is the standard primary treatment of gastric cancer. Unfortunately, most patients are already in the advanced stage of the disease when they are diagnosed with gastric cancer. Alternative therapies, such as radiation therapy and chemotherapy, can achieve only very limited benefits. The emergence of cancer drug resistance has always been the major obstacle to the cure of tumors. The main goal of modern cancer pharmacology is to determine the underlying mechanism of anticancer drugs. Objective: Here, we mainly review the latest research results related to the mechanism of chemotherapy resistance in gastric cancer, the application of natural products in overcoming the chemotherapy resistance of gastric cancer, and the new strategies currently being developed to treat tumors based on immunotherapy and gene therapy. Conclusion: The emergence of cancer drug resistance is the main obstacle in achieving alleviation and final cure for gastric cancer. Mixed therapies are considered to be a possible way to overcome chemoresistance. Natural products are the main resource for discovering new drugs specific for treating chemoresistance, and further research is needed to clarify the mechanism of natural product activity in patients. 

Sign in / Sign up

Export Citation Format

Share Document