scholarly journals Host-Directed Antiviral Therapy

2020 ◽  
Vol 33 (3) ◽  
Author(s):  
Naveen Kumar ◽  
Shalini Sharma ◽  
Ram Kumar ◽  
Bhupendra N. Tripathi ◽  
Sanjay Barua ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Drug Development ◽  
Virus Replication ◽  
Antiviral Drug ◽  
Antiviral Agent ◽  
Drug Resistant ◽  
Virus Infections ◽  
Alternate Host ◽  
Cellular Factors ◽  
Rapid Generation

SUMMARY Antiviral drugs have traditionally been developed by directly targeting essential viral components. However, this strategy often fails due to the rapid generation of drug-resistant viruses. Recent genome-wide approaches, such as those employing small interfering RNA (siRNA) or clustered regularly interspaced short palindromic repeats (CRISPR) or those using small molecule chemical inhibitors targeting the cellular “kinome,” have been used successfully to identify cellular factors that can support virus replication. Since some of these cellular factors are critical for virus replication, but are dispensable for the host, they can serve as novel targets for antiviral drug development. In addition, potentiation of immune responses, regulation of cytokine storms, and modulation of epigenetic changes upon virus infections are also feasible approaches to control infections. Because it is less likely that viruses will mutate to replace missing cellular functions, the chance of generating drug-resistant mutants with host-targeted inhibitor approaches is minimized. However, drug resistance against some host-directed agents can, in fact, occur under certain circumstances, such as long-term selection pressure of a host-directed antiviral agent that can allow the virus the opportunity to adapt to use an alternate host factor or to alter its affinity toward the target that confers resistance. This review describes novel approaches for antiviral drug development with a focus on host-directed therapies and the potential mechanisms that may account for the acquisition of antiviral drug resistance against host-directed agents.

scholarly journals Cytomegalovirus Replication Steps and the Actions of Antiviral Drugs

2018 ◽  
Vol 16 (2) ◽  
pp. 80-95 ◽  
Author(s):  
Ashwaq Ahmed Abdullah ◽  
Krishnan Nair Balakrishnan ◽  
Jamilu Abubakar Bala ◽  
Faez Firdaus Jesse Abdullah ◽  
Zeenatul Allaudin Nazariah ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Virus Replication ◽  
Human Cytomegalovirus ◽  
Adverse Reactions ◽  
Antiviral Drug ◽  
Antiviral Drugs ◽  
Active Infection ◽  
Detailed Understanding ◽  
Cellular Factors ◽  
Antiviral Drug Resistance

Human cytomegalovirus (HCMV) is a beta herpesvirus that inflicts an active infection in the fetus and immunosuppressive patients. The virus encodes many proteins that work together with cellular factors to achieve virus replication. In addition to vaccines, antiviral drugs can be deployed to manipulate how the virus replicates and minimize its pathogenicity. The five antiviral drugs approved by the Food and Drug Administration (FDA) have shown adverse reactions and the antiviral drug resistance were reported. Hence, this warrants the need for urgent development of a novel antiviral drug. Detailed understanding of the virus replication steps and how cellular signals interact with these steps will be key for pharmacological developments of for anti HCMV drugs. This review summarized all the drugs that target the virus proteins and cell signals that mediate CMV replication.

scholarly journals Escape Mutations in NS4B Render Dengue Virus Insensitive to the Antiviral Activity of the Paracetamol Metabolite AM404

2016 ◽  
Vol 60 (4) ◽  
pp. 2554-2557 ◽  
Author(s):  
Koen W. R. van Cleef ◽  
Gijs J. Overheul ◽  
Michael C. Thomassen ◽  
Jenni M. Marjakangas ◽  
Ronald P. van Rij
Keyword(s):  
Antiviral Activity ◽  
Drug Development ◽  
Dengue Virus ◽  
Virus Replication ◽  
Disease Burden ◽  
Antiviral Drug ◽  
Virus Infections ◽  
Antiviral Compounds

ABSTRACTDespite the enormous disease burden associated with dengue virus infections, a licensed antiviral drug is lacking. Here, we show that the paracetamol (acetaminophen) metabolite AM404 inhibits dengue virus replication. Moreover, we find that mutations in NS4B that were previously found to confer resistance to the antiviral compounds NITD-618 and SDM25N also render dengue virus insensitive to AM404. Our work provides further support for NS4B as a direct or indirect target for antiviral drug development.

European Training Network on (+)RNA Virus Replication and Antiviral Drug Development

2011 ◽  
Vol 90 (2) ◽  
pp. A64
Author(s):  
Frank van Kuppeveld ◽  
Eric Snijder ◽  
Alexander Gorbalenya ◽  
Bruno Canard ◽  
Ralf Bartenschlager ◽  
...  
Keyword(s):  
Drug Development ◽  
Virus Replication ◽  
Rna Virus ◽  
Antiviral Drug ◽  
European Training

scholarly journals Differential Transmission of Antiviral Drug-Resistant Chikungunya Viruses by Aedes Mosquitoes

mSphere ◽  
2018 ◽  
Vol 3 (4) ◽  
Author(s):  
Leen Delang ◽  
Pei-Shi Yen ◽  
Thomas Vallet ◽  
Marie Vazeille ◽  
Marco Vignuzzi ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Aedes Aegypti ◽  
Chikungunya Virus ◽  
Antiviral Drug ◽  
Antiviral Drugs ◽  
Wild Type Virus ◽  
Drug Resistant ◽  
Wild Type ◽  
Resistant Genotype ◽  
Content Type

ABSTRACT The chikungunya virus (CHIKV) is transmitted by female Aedes aegypti and Aedes albopictus mosquitoes, mostly present in (sub)tropical regions. No antivirals are available to treat CHIKV infections. If antiviral drugs are proven efficient to treat CHIKV-infected patients, it will be pivotal to determine whether drug-resistant viruses can be transmitted from one human to another by their mosquito vectors. We orally infected Aedes aegypti mosquitoes with a blood meal containing wild-type or drug-resistant CHIKV variants (i.e., MADTPres CHIKV, with mutation in the nsP1 gene, and T-705res CHIKV, with mutation in the RNA-dependent RNA polymerase [RdRp] gene). Viral loads were quantified in bodies (infection), heads (dissemination), and saliva (transmission) of individual mosquitoes. The infection rate of the resistant viruses was similar to that of the wild-type virus. However, the dissemination of T-705res CHIKV was markedly decreased compared to wild-type and MADTPres CHIKV. Furthermore, T-705res CHIKV was only transmitted in the saliva at day 20 postinfection (p.i.), whereas transmission of wild-type CHIKV was observed at day 3 p.i. The attenuated phenotype of the T-705res virus was confirmed in mosquito cell culture, whereas the replication fitness in Vero cells was similar to that of the wild type. In bodies and heads of mosquitoes infected with the resistant variants, the resistant phenotype and genotype were retained. Also in the saliva, the resistant genotype of MADTPres CHIKV was maintained. Our results illustrate that the fitness of drug-resistant variants should be evaluated in both hosts to be able to select antiviral drugs with a limited risk for the spread of drug resistance by mosquitoes. IMPORTANCE Because of its global reemergence and unusual morbidities associated with infection, the chikungunya virus (CHIKV) has become a substantial public health problem. However, no antivirals are currently available to treat CHIKV infections. If antiviral drugs will prove to be efficient to treat CHIKV-infected patients, it will be essential to understand if drug-resistant viruses can be transmitted from one human to another by the mosquito. We therefore orally infected Aedes mosquitoes with drug-resistant CHIKV variants and determined the replication and transmission levels. One of the antiviral drug-resistant CHIKV variants could efficiently replicate and disseminate in both laboratory and field-collected mosquitoes. In addition, this variant retained its drug-resistant genotype in the saliva. In contrast, the other drug-resistant variant was markedly attenuated in mosquitoes. Our results illustrate that extra caution for drug resistance should be considered when developing an antiarbovirus antiviral in order to minimize the risk of spreading drug resistance by mosquitoes.

Pharmacologic Considerations for Antiviral Drug Development

1996 ◽  
Vol 30 (9) ◽  
pp. 972-977 ◽  
Author(s):  
Courtney V Fletcher
Keyword(s):  
Drug Development ◽  
Mechanism Of Action ◽  
Rapid Development ◽  
Antiviral Agents ◽  
Antiviral Drug ◽  
Antiviral Agent ◽  
Inoculum Size ◽  
Kidney Transplant Recipients ◽  
Therapeutic Success ◽  
Early Integration

OBJECTIVE: To discuss pharmacologic considerations for the development of antiviral agents. DATA SOURCES: English-language literature pertaining to the development and clinical evaluation of antiviral compounds, primarily agents targeted against herpes group viruses and HIV. STUDY SELECTION AND DATA EXTRACTION: Pertinent information, as judged by the author, was selected for discussion. DATA SYNTHESIS: Drug development of antiviral agents presents unique problems compared with that of antimicrobial and other agents. Understanding the mechanism of action and both pharmacokinetic and pharmacodynamic considerations is critical to developing a rational dosing strategy and safe, effective use. The lack of standardized methods for antiviral susceptibility testing and the influence of factors such as strain of virus, host cell type, culture medium, inoculum size, end point, and method of measurement on the results obtained illustrate factors that complicate preclinical pharmacologic analysis of antiviral agents. Acyclovir offers a model for clinical drug development. Its mechanism of action, pharmacokinetics, and pharmacodynamics have been studied extensively. Rational guidelines for usage are available, including guidelines in special patient populations such as kidney transplant recipients and neonates. A pregnancy registry has allowed evaluation of the incidence of birth defects in fetuses exposed to systemic acyclovir. Several pitfalls in antiviral drug development are associated with inadequate pharmacologic information. The development of dextran sulfate and fialuridine provides two examples. Integration of pharmacokinetic and pharmacodynamic analyses using modern sampling and analysis techniques may facilitate more rapid development of antiviral agents and more informed dosage regimens to achieve the highest probability of therapeutic success. CONCLUSIONS: Insufficient knowledge of the pharmacokinetic and pharmacodynamic characteristics of an antiviral agent is a barrier to efficient drug development. Application and early integration of pharmacologic information into clinical investigations hold promise as a means to shorten the development process and, more importantly, to arrive at informative dosing regimens that optimize therapeutic success.

Candida auris and Nosocomial Infection

2020 ◽  
Vol 21 (4) ◽  
pp. 365-373 ◽  
Author(s):  
Sweety Dahiya ◽  
Anil K. Chhillar ◽  
Namita Sharma ◽  
Pooja Choudhary ◽  
Aruna Punia ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Pathogenic Fungus ◽  
Control Measures ◽  
Whole Genome Sequence ◽  
Whole Genome ◽  
Drug Resistant ◽  
Candida Auris ◽  
Preventive Control ◽  
Identification Techniques ◽  
Sensitivity Profile

The existence of the multi-drug resistant (MDR) pathogenic fungus, Candida auris came to light in 2009. This particular organism is capable of causing nosocomial infections in immunecompromised persons. This pathogen is associated with consistent candidemia with high mortality rate and presents a serious global health threat. Whole genome sequence (WGS) investigation detected powerful phylogeographic Candida auris genotypes which are specialized to particular geological areas indicating dissemination of particular genotype among provinces. Furthermore, this organism frequently exhibits multidrug-resistance and displays an unusual sensitivity profile. Identification techniques that are commercialized to test Candida auris often show inconsistent results and this misidentification leads to treatment failure which complicates the management of candidiasis. Till date, Candida auris has been progressively recorded from several countries and therefore its preventive control measures are paramount to interrupt its transmission. In this review, we discussed prevalence, biology, drug-resistance phenomena, virulence factors and management of Candida auris infections.

Fanconi Anemia DNA Repair Pathway as a New Mechanism to Exploit Cancer Drug Resistance

2020 ◽  
Vol 20 (9) ◽  
pp. 779-787
Author(s):  
Kajal Ghosal ◽  
Christian Agatemor ◽  
Richard I. Han ◽  
Amy T. Ku ◽  
Sabu Thomas ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Dna Repair ◽  
Fanconi Anemia ◽  
Cancer Drug ◽  
Drug Resistant ◽  
Cancer Drugs ◽  
Repair Pathway ◽  
Cancer Drug Resistance ◽  
Anti Cancer ◽  
Cancerous Cells

Chemotherapy employs anti-cancer drugs to stop the growth of cancerous cells, but one common obstacle to the success is the development of chemoresistance, which leads to failure of the previously effective anti-cancer drugs. Resistance arises from different mechanistic pathways, and in this critical review, we focus on the Fanconi Anemia (FA) pathway in chemoresistance. This pathway has yet to be intensively researched by mainstream cancer researchers. This review aims to inspire a new thrust toward the contribution of the FA pathway to drug resistance in cancer. We believe an indepth understanding of this pathway will open new frontiers to effectively treat drug-resistant cancer.

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