explain the difficulties in developing antiviral drugs against dna viruses, when compared to rna viruses.
James
Guys, does anyone know the answer?
get explain the difficulties in developing antiviral drugs against dna viruses, when compared to rna viruses. from EN Bilgi.
Antiviral drug resistance as an adaptive process
Antiviral drug resistance is a matter of great clinical importance that, historically, has been investigated mostly from a virological perspective. Although the proximate mechanisms of resistance can be readily uncovered using these methods, larger evolutionary ...
Virus Evol. 2016 Jan; 2(1): vew014.
Published online 2016 Jun 10. doi: 10.1093/ve/vew014
PMCID: PMC5499642 PMID: 28694997
Antiviral drug resistance as an adaptive process
Kristen K. Irwin,1,2 Nicholas Renzette,3 Timothy F. Kowalik,3 and Jeffrey D. Jensen1,2
Author information Copyright and License information Disclaimer
This article has been cited by other articles in PMC.
Associated Data
Supplementary Materials
Go to:
Abstract
Antiviral drug resistance is a matter of great clinical importance that, historically, has been investigated mostly from a virological perspective. Although the proximate mechanisms of resistance can be readily uncovered using these methods, larger evolutionary trends often remain elusive. Recent interest by population geneticists in studies of antiviral resistance has spurred new metrics for evaluating mutation and recombination rates, demographic histories of transmission and compartmentalization, and selective forces incurred during viral adaptation to antiviral drug treatment. We present up-to-date summaries on antiviral resistance for a range of drugs and viral types, and review recent advances for studying their evolutionary histories. We conclude that information imparted by demographic and selective histories, as revealed through population genomic inference, is integral to assessing the evolution of antiviral resistance as it pertains to human health.
Keywords: antiviral resistance, genetic barrier, mutagenesis, fluctuating selection, compensatory mutation, cost of adaptationGo to:
1. Resistance as an evolutionary process
Viral evolution, with its many public health consequences, is increasingly investigated within a population genetic framework. The growing availability of high quality molecular data has changed the scale at which these evolutionary processes can be monitored. Parameters such as nucleotide diversity, the strength of selection, and effective population size (Ne) can be monitored almost in real time using experimental evolution, and can be measured at increasingly frequent intervals in patients, informing treatment decisions (Chevillotte et al. 2010; Newman et al. 2013; Renzette et al. 2014). New mutations can also be observed at a fine scale, and of particular interest are those conferring drug resistance (Moya et al. 2004; zur Wiesch et al. 2011).
An increasing number of viral infections that impair host health are treated using antiviral drugs, typically targeting mechanisms of viral replication (Fig. 1). If the treatment is robust and viral fitness is impaired sufficiently, no viral genomes will be successfully replicated, but if treatment is not as effective and some genomes replicate, selective pressure may result in rapid adaptation toward resistance. This is exacerbated by the large population sizes and high rates of mutation characterizing many viruses: if resistance-conferring polymorphisms do not already exist in the population at the onset of treatment, they will likely arise soon thereafter. This problem has forced antiviral drug development to remain innovative, including combining existing drugs, and establishing new drug classes.
Figure 1.
Depictions of viral replication and protein synthesis. Representative replication mechanisms for DNA viruses HSV and HCMV, RNA viruses HCV and IAV, lentivirus HIV, and HBV. Bright blue strands represent viral DNA, green strands represent viral RNA, pink shapes represent virally produced enzymes, and purple shapes represent host-produced enzymes. When necessary, positive and negative-sense RNAs are designated with (+) and (−), respectively; note that only positive-sense RNA can be directly translated into proteins. Arrows indicate transcription, translation, replication, or integration activity, as denoted either by descriptive grey text or by the nearest enzyme. Bold, italicized text indicates drug classes for which known resistance mutations occur; the nearest enzyme (or replicative process) indicates the target of that drug class.
We here present a brief review of resistance mechanisms and their evolution, with a focus on viruses relevant to human health; we continue by describing evolutionary forces that are uniquely exemplified by viral resistance, and thus merit special attention from both the population genetics and virology fields.
Go to:
2. Variation in viral biology and resistance mechanisms
Differences in viral replication biology drive the generation of new drug classes targeting different parts of the viral life cycle. Understanding these differences is critical not only for synthesizing new drugs, but also for predicting and countering evolution towards resistance, Below, we briefly review common modes of resistance (and relevant underlying biology) in six exemplary viruses: RNA viruses hepatitis C and influenza A virus (IAV), DNA viruses herpes simplex virus (HSV) and human cytomegalovirus (HCMV), retrovirus HIV, and unconventionally replicating hepatitis B virus (HBV).
Hepatitis C virus (HCV) is characterized by a high mutation rate and subsequently high genomic diversity (Simmonds 2004) (Table 1). This mutation rate is facilitated by frequent replication and poor proofreading function of the virally encoded RNA polymerase. In fact, the virus likely exists as a quasispecies, or a group of genomes forming a structured ‘cloud’ in sequence space, with replication near the maximum error rate allowed before genomic integrity is lost (Sanjuán et al. 2004; Eigen 2002). Within a host, HCV replicates in different compartments, such as different organs or bodily fluids (Halfon and Locarnini 2011). Bottlenecks are common during both inter-host transmission and intra-host compartmentalization (Bull et al. 2011); these bottlenecks reduce population size, thus amplifying the role of genetic drift in HCV evolution (Table 1). The most common antiviral drugs used against HCV are direct-acting antiviral agents (DAAs), which usually inhibit either protease or polymerase activity. Those inhibiting protease have a low genetic barrier to resistance, meaning that resistance is easily achieved through only one or a few mutations (see Section 4). Indeed, given the high rate of mutation, it is likely that these polymorphisms may already exist in a given population (Bull et al. 2011). However, new combinations of the DAAs, such as ledipasvir and sofosbuvir (marketed as Harvoni), appear to have a high genetic barrier to resistance, with very little (if any) cross-resistance between the two drugs, and are thus promising for future treatment (Gritsenko and Hughes 2015).
Developing antiviral drugs is not easy – here's why
The UK government has created an antivirus taskforce to develop new drugs against coronavirus.
Pavol Bardy, Fred Anston, Oliver Bayfield, University of York
The UK prime minister, Boris Johnson, recently announced the creation of an antivirus taskforce to “supercharge” the development of new antiviral drugs. At a Downing Street press conference, Johnson said: “The majority of scientific opinion in this country is still firmly of the view that there will be another wave of COVID at some stage this year.” The prime minister hopes to have antiviral drugs ready by the autumn to help quell this third wave.
While there are anti-inflammatory drugs that reduce the risk of death from COVID, such as dexamethasone and tocilizumab, they are only given to people hospitalised with severe COVID. But Johnson wants drugs that can be taken at home, in pill form, that stop people ending up in hospital on a ventilator.
It usually takes years to develop and approve new antiviral drugs because the discovery pipeline involves a painstaking process of identifying chemical compounds that target the virus and then testing their efficacy and safety. For this reason, scientists are also looking at reusing existing drugs that have been approved for treating other viruses or diseases.
Unlike broad-spectrum antibiotics, which can be used to treat a wide range of bacterial infections, drugs that work against one type of virus rarely work at treating other viruses. For example, remdesivir, originally developed for treating hepatitis C, was at one point suggested as a treatment for COVID, but clinical trials have shown that it has only a limited effect against this coronavirus.
The reason there are few effective broad-spectrum antivirals is that viruses are much more diverse than bacteria, including in how they store their genetic information (some in the form of DNA and some as RNA). Unlike bacteria, viruses have fewer of their own protein building blocks that can be targeted with drugs.
For a drug to work, it has to reach its target. This is particularly difficult with viruses because they replicate inside human cells by hijacking our cellular machinery. The drug needs to get inside these infected cells and act on processes that are essential for the normal functioning of the human body. Unsurprisingly, this often results in collateral damage to human cells, experienced as side-effects.
Targeting viruses outside cells – to stop them from gaining a foothold before they can replicate – is possible, but is also difficult because of the nature of the virus shell. The shell is extraordinarily robust, resisting the negative effects of the environment on the way to its host. Only then does it decompose or eject its content, which contains its genetic information.
This process may be a weak spot in the virus lifecycle, but the conditions that are in the control of the release are very specific. While drugs targeting the virus shell sounds appealing, some may still be toxic to humans.
Difficult but not impossible
Despite these difficulties, drugs that treat viruses such as influenza and HIV have been developed. Some of these drugs target the processes of viral replication and the viral shell assembly. Promising drug targets of coronaviruses have been identified as well. But developing new drugs takes a long time, and viruses mutate quickly. So even when a drug is developed, the ever-evolving virus might soon develop resistance towards the drug.
A further problem in fighting viruses is that several viruses – such as HIV, papillomavirus and herpes – can switch into a sleeping mode. In this state, infected cells don’t produce any new viruses. The genetic information of the virus is the only viral thing present in the cells. Drugs interfering with the replication or shell of the virus do not have anything to be active against, so the virus survives.
When the sleeping virus becomes active again, symptoms are likely to reoccur and additional treatment with a drug is then necessary. This increases the chance of the drug resistance developing, since the virus experiences the drug-induced selection for resistant variants for a longer time.
Although we are still only starting to understand the lifecycle of coronaviruses, there are signs that they can persist for an extended time, particularly in patients with weak immunity, resulting in an additional problem of generating more resistant virus strains.
Research on understanding how the coronavirus works has come a long way, in a short time, but when it comes to developing antivirals there are still many questions to be answered. With a potential resurgence in infections expected later in the year, the antiviral taskforce has its work cut out.
Antiviral drugs Coronavirus COVID-19 Remdesivir
Coronavirus insights
Before you go …
90,000 experts have written for The Conversation. Because our only agenda is to rebuild trust and serve the public by making knowledge available to everyone rather than a select few. Now, you can receive the latest articles in your inbox every day. Give it a go?
Jo Adetunji
Editor, The Conversation UK
You might also like
Will coronavirus really evolve to become less deadly?
Will coronavirus really evolve to become less deadly? All the coronavirus in the world could fit inside a Coke can, with plenty of room to spare
Test 2. essay questions Flashcards
Start studying Test 2. essay questions. Learn vocabulary, terms, and more with flashcards, games, and other study tools.
Test 2. essay questions
How is hydrogen peroxide antimicrobial?
Click card to see definition 👆
Hydrogen peroxide has oxygen as it chemical component which is highly reactive giving it the ability to act as an antimicrobial. Also it is a very strong oxidizing agent enabling to change the chemical structure of many substances. Hydrogen peroxide are able to kill bacteria easily because it is able to oxidized the cell wall of the bacteria leaving them unprotected and eventually die. When hydrogen peroxide is pour on a wound it helps it slow the bleeding in the area by closing off the capillaries and blood vessels. It is also a very affordable and accessible disinfectant which makes it an ideal antimicrobial agent.
Click again to see term 👆
Assume that you are responsible for decontaminating materials in a large hospital. How would you sterilize each of the following? Briefly justify your answers.
a. a mattress used by a patient with bubonic plague.
b. intravenous glucose-saline solutions
c. used disposable syringes
d. tissues taken from patients
Click card to see definition 👆
a) UV radiation,Hepa vacuuming .kill vegetative forms of bacterial pathogen, viruses, and fungi
b) Heat sterilization by autoclave. sterile solutions by killing bacteria without affecting the solution
c)Ethylene oxide
d) gas sterilization.the gas can penetrate the tissue
Click again to see term 👆
1/6 Created by vtran0828
Terms in this set (6)
How is hydrogen peroxide antimicrobial?
Hydrogen peroxide has oxygen as it chemical component which is highly reactive giving it the ability to act as an antimicrobial. Also it is a very strong oxidizing agent enabling to change the chemical structure of many substances. Hydrogen peroxide are able to kill bacteria easily because it is able to oxidized the cell wall of the bacteria leaving them unprotected and eventually die. When hydrogen peroxide is pour on a wound it helps it slow the bleeding in the area by closing off the capillaries and blood vessels. It is also a very affordable and accessible disinfectant which makes it an ideal antimicrobial agent.
Assume that you are responsible for decontaminating materials in a large hospital. How would you sterilize each of the following? Briefly justify your answers.
a. a mattress used by a patient with bubonic plague.
b. intravenous glucose-saline solutions
c. used disposable syringes
d. tissues taken from patients
a) UV radiation,Hepa vacuuming .kill vegetative forms of bacterial pathogen, viruses, and fungi
b) Heat sterilization by autoclave. sterile solutions by killing bacteria without affecting the solution
c)Ethylene oxide
d) gas sterilization.the gas can penetrate the tissue
Explain the difficulties in developing antiviral drugs against DNA viruses, when compared to RNA viruses
RNA viruses have an enzyme called reversed transcriptase to replicate it genetic material but lack the ability for checking errors therefore have higher mutation rate. It is harder to treat RNA viruses because of their mutation rate so when a treatment is created to treat it it will be ineffective because the viruses would have mutated again. Although the mutation rate is high in RNA viruses their enzyme are targeted to make vaccine or medication to fight it.In DNA viruses have no reverse transcriptase because they use the nucleus of the host cell to replicate their genetic material. DNA viruses protein are much similar to human protein so it is difficult to treat it without harming the host cells.
-have different enzymes for replication (RNA), DNA viruses use host machinery or similar processes for replication. not all rna viruses use reverse transcriptase
Scientists are concerned that bacteria will be resistant to all antibiotics within the next decade. Using your knowledge of genetics, describe how bacterial populations can develop drug resistance in such a short time frame.
There are a number of ways that bacteria becomes resistant to antimicrobial. There is spontaneous mutation for antibiotic resistant which is acquired over many generations. Bacteria cell have a tiny circular DNA called the plasmid that carry the resistant gene. The plasmid contribute to the synthesis of proteins that degrade and modified antibiotic.In addition it also produce proteins that makes up the efflux pump which helps to flush out antibiotic in the cell. Transformation, transduction, and conjugation also contributes to bacteria resistant to antibiotic.The overuse of antibiotic and over-cleanliness can also be factors of bacteria resistance because the killing of nonresistant bacteria cause the small percentage of bacteria that did survived to mutate and become stronger.
What is the survival value of the semiconservative replication of DNA?
redundancy and increased ability to repair
How is the replication of the viral genome of retroviruses unique among the viruses?
the virus carry an enzyme called reverse transcriptase which uses the viral RNA as a template to make double stranded DNA which is then inserted into the host genome. The virus can remain in the lysogenic cycle and remains in a latent state and replicates when the host cell replicate or it can be or jump to a lytic cycle where it replicates and kill the host cell.
Guys, does anyone know the answer?