Antiviral - Hepatitis C

Surname 1

Student’s Name

Professor’s Name

Course

Date

Table of Contents

The Nature of Hepatitis C and the Conditions that are treated by DAAs... Error! Bookmark

not defined.

Fig. 1: Specific Targets of the Direct Acting Antiviral Agents ........................................... 3

The History of the Development of DAAs .................................................................................. 4

The Mechanism of DAAs’ Action (NS3/4A Protease Inhibitors (PIs), telaprevir, Nucleotide

NS5B inhibitor, Sofosbuvir and NS5A inhibitor, Daclatasvir) Relating it to the Content of

the Nature of the Disease/Condition ............................................................................................ 6

Stereo-Chemical and Conformational Requirements of Drug-Target Interactions ........... 6

Telaprevir Mechanism of Action ......................................................................... 7

Sofosbuvir Mechanism of Action ......................................................................... 8

Daclatasvir Mechanism of Action........................................................................ 8

The Quantitative Structure-Activity Relationships Relevant to Telaprevir Illustrated with

its Chemical Structure .................................................................................................................. 9

Fig. 5: Chemical Structure of Telaprevir ......................................................................... 10

Fig. 6: QSAR Tables ......................................................................................................... 11

Works Cited .................................................................................................................................. 13

Surname 2

Antiviral - Hepatitis C

The Nature of Hepatitis C

Hepatitis C refers to inflammation of the liver, and it is caused by Hepatitis C Virus

(HCV). HCV is a small positive-strand ribonucleic acid (RNA) virus in the Flaviviridae family.

There are several different HCV genotypes with the most common one in the U.S.A being HCV

genotype 1. The rate of new infection with HCV is estimated to be between 3-4 million

individuals each year (WHO 2017). Hepatitis C is the main cause of many deaths each year in

the U.S and other parts of the world. The human immune system cannot easily eliminate the

HCV from the body due to its rapid rate of replication hence the infection usually becomes

chronic (medicaleconomics). If left untreated, Hepatitis C can cause serious damages to the liver

and lead to liver failure. Nevertheless, modern treatments have made it possible to cure Hepatitis

C infection, thus giving most people with it the hope of a normal life expectancy. This paper will

hence dwell on antiviral drugs(NS3/4A Protease Inhibitors (PIs), telaprevir, Nucleotide NS5B

inhibitor, Sofosbuvirand NS5A inhibitor, Daclatasvir) which are used to cure the Hepatitis C

infection and the conditions that the drugs can be used to treat.

HCV is a blood borne virus, and one can be infected with it through exposure to infected

blood. Organ transplants, blood transfusions, and sharing of sharp objects are common ways

through which the virus can be spread. The infection may be short-lived in some people as their

body can clear the virus without treatment. Usually, there are no noticeable symptoms when the

virus first enters the body, and many people may have the infection without realizing it (NCBI).

The symptoms may develop gradually right from the acute stage of Hepatitis C. If the infection

lingers in the body for six months or longer, symptoms such as fever, appetite loss and tiredness

may be experienced by the infected person. The only way to be certain whether one has been

infected or not is through testing.

Since the discovery of Hepatitis C in 1989, many advances have been made in developing

safe and effective treatments. The development of Direct-Acting Antivirals (DAAs) has

significantly improved the efficacy of treatments for HCV infection. These drugs target HCV

and stop its replication at various stages of the virus life cycle (Halfon). By preventing HCV

from making copies of itself, the virus can eventually be eliminated from the body. DAAs stop

the virus from reproducing and can clear the HCV in a matter of two weeks. This way, the

danger of liver inflammation and liver failure after a severe attack by the virus is eliminated.

Surname 3

HCV infection is likely the leading cause of chronic liver-related diseases such as hepatocellular

carcinoma, liver failure, and liver cirrhosis. DAAs stop the damage of the liver by getting rid of

the virus that is responsible for the damage.

The DAAs are categorized into four classes. They include NS3/4A Protease Inhibitors

(PIs), Nucleoside and Nucleotide NS5B Polymerase Inhibitors, NS5A Inhibitors, and Non-

Nucleoside NS5B Polymerase Inhibitors (hepctip.ca). NS3/4A Protease Inhibitors (PIs) prevent

HCV from replicating in the host cell by blocking protease, a viral enzyme. Nucleoside and

Nucleotide NS5B Polymerase Inhibitors attach themselves onto RNA, thereby blocking the virus

from multiplying. NS5A Inhibitors block NS5A which is a protein that HCV needs to reproduce

and for the various stages of infection (Jakobsen et al.). Non-Nucleoside NS5B Polymerase

Inhibitors attach themselves to HCV so that other pieces cannot attach themselves to it. DAAs

work by inhibiting specific stages of the HCV replication cycle

Fig. 1: Specific Targets of the Direct Acting Antiviral Agents

Adopted from (Jakobsen).

The NS5B polymerase and NS3-4A protease target active sites of the viral enzyme which

are essential for replication (Gardner). The NS5A protein inhibits the activities of NS5A. DAAs

Surname 4

have fewer side effects and relatively higher efficacy with shorter treatment times. These host-

targeting antivirals have Sustained Viral Reaction (SVR) rate of up to 95%. Before treatment

with DAA drugs, factors such as baseline viral load, HCV genotype and virological response to

treatment need to be considered (Delang). Eradication of HCV before a liver transplant can lead

to improved efficacy. DAAs treatment can take 8-12 weeks to eliminate the HCV from the body.

The History of the Development of DAAs

Unlike antibiotics which achieved an advanced therapeutic stage in 30 years, Antiviral

chemotherapy has advanced at a slow pace. Antiviral development took 60 years to reach its

current status of effectiveness (Bryan-Marrugo et al.). The evolution of Hepatitis C treatment has

shown how the development of Antiviral is a very complex process. Combined and specific

targeted antiviral therapy has proved to be the best approach for the treatment of a viral disease.

A thorough description of the development of specifically targeted antiviral therapy can be

useful for further research and treatment of viral diseases.

The number of new viruses that have been identified as causative agents of human

diseases since 1972 is more than 50. More sophisticated therapeutic agents are required to

combat these new viral diseases (Gane). Unfortunately, the development of these strategies has

been slow and full of hurdles. The development of DAAs has come a long way. A standard of

care (SOC) between 2001 and 2011 consisted a combination of ribavirin (RBV) and pegylated

interferon (PEG-IFN) (Strader and Seeff). The lingering response rates of HCV genotype 1 to

ribavirin (RBV) and pegylated interferon (PEG-IFN) treatment led to investigations to develop

therapies that focus on the virus itself. The first-generation NS3/4A protease inhibitors,

telaprevir, and boceprevir, were authorized for use in combination with RBV and PEG-IFN in

May 2011(Fung). The HCV genotype 1 treatment using these combinations was to take 24-48

weeks.

In December 2013, a second-generation NS3/4A protease inhibitor, Simeprevir was

approved for use in combination with RBV and PEG-IFN for 12 weeks treatment course in HCV

genotype 1(Graham). An NS5B nucleotide polymerase inhibitor, Sofosbuvir was also approved

in 2013 for use in combination with RBV and PEG-IFN for 12-24 weeks treatment course in

HCV genotype 1 to 4 (Catherine). IFN free regimens were later found to be more effective and

Surname 5

gave better results. A combination of simeprevir or NS5A replication complex inhibitor,

daclatasvir or ledipasvir with Sofosbuvir with or without RBV for a 12 weeks treatment course

in HCV genotype1 saw a sustained virological response (SVR) of more than 90% (Lin).

Additionally, regimens based on ritonavir-boosted NS3/4A protease inhibitor, ABT-450/r

combined with or without RBV for 12 weeks treatment course in HCV genotype 1 have also

produced similar results (Rosenquist).

Development of NS3/4A Protease Inhibitors (PIs), telaprevir faced a lot of hurdles as it

had to be put on hold due to its performance in a standard IC

assay. It took data from new

experiments and hypothesis to justify further investment in the development of telaprevir. The

drug was approved in Europe in 2011 for the treatment of HCV genotype 1. Nucleotide NS5B

inhibitor, Sofosbuvir, also known, as GS-7977 discovery revolutionized the management of

Hepatitis C Virus infection. It was used in the initial evaluation with RBV and PEG-IFN. The

valuable features of Sofosbuvir which include its excellent tolerability, pan genotypic activity,

and safety profile makes it a powerful weapon in the treatment of HCV infection (Zappulo). The

highly selective NS5A inhibitor, Daclatasvir (BMS790052) was developed by Bristol-Myers

Squibb. It has a broad coverage of HCV genotypes in vitro. Daclatasvir (BMS790052 was

approved in July 2015 for use in treatment of HCV genotype 1 and 3

Therapy for HCV infection was at the pace of snail as it remained nearly the same

between 2001 and 2011. The development of specific compounds against HCV took a very long

time. The hurdles that slowed the process include the limitation of animal models for

experimentation and in vitro systems. Also, there was a low rate of discovery of suitable

candidate molecules and the balance between resistance to the selected antiviral drugs, toxicity,

and efficacy. The development of an in vitro virus propagation system by Weller, Robbins, and

Enders in 1951 was a huge breakthrough in this field. This helped in the study of viruses. The

inception of 9-(2-hydroxy ethoxy methyl) guanine (Acyclovir) improved the understanding of

virus-host interaction. It was the first highly effective antiviral drug.

DAAs approval has substantially improved therapeutic options for treatment of HCV

infection. An era of development of new DAAs for HCV treatment is currently emerging.

Several other Direct-acting antivirals are being developed such as Protease inhibitors:

asunaprevir, faldaprevir, vaniprevir, danoprevir, GS-9451, MK5172, ABT-450-ritonavir; NS5A

inhibitors:daclatasvir, MK-8742, PPI-668, GS-5816, ombitasvir and ledipasvir; NS5b

Surname 6

inhibitors:GS-9669, BMS-791325, dasabuvir, VX-135, and mericitabine. These have been

shown to reduce viral RNA levels with upto 95% SVR in treated patients (Clercq E). DAAs have

to overcome the main obstacles of drug resistance and HCV genetic variability.

Antiviral therapy is well established and shows a promising future. Depending on

medical, economic and scientific interest, development of antiviral drugs in the coming years

will majorly focus on HCV and HIV. The increase in knowledge about viruses, their lifecycle,

structure, pathogenesis, function, infection mechanism and rapid discovery of antiviral strategies

and techniques will speed up the development of antiviral drugs (Akimitsu). Antiviral drugs have

brought a dramatic paradigm shift in the space of a few years. HCV infection which was once

very difficult to cure has become easily curable with a short duration of oral antiviral therapy

with minimal side effects.

Mechanism of Action

Stereo-Chemical and Conformational Requirements of Drug-Target Interactions.

Stereochemistry has become a significant issue in recent years not only to the pharmaceutical

industry but also to the regulatory authorities. It is important for drug manufacturers to consider

stereo selectivity when designing small molecules to interact with the targets. The pharmacologic

basis of drug action majorly involves modulation of the physiological activities of

macromolecules such as ribosomes, receptors, and enzymes by binding them to the drug

molecules. The temporal persistence of target occupancy by the drug dictates the duration of

pharmacologic effect. Historically, the effectiveness of a drug's interaction with a target has often

been quantified by measuring the concentration of drug required to achieve a specific level of

target occupancy under equilibrium conditions (Mehnaz). In recent years, there has been

increased recognition that equilibrium conditions do not define drug-target interactions in vivo.

The binary drug-target complex is stabilized in vivo to achieve sustained pharmacologic effect.

The reaction of drugs with receptors as specific tissues is a very important goal when

designing drugs. Recent techniques such as molecular modeling can be used to search structures

that show specificity for the target receptor that will produce the desired pharmacological

response while decreasing the affinity for undesired receptors that produce adverse response

Surname 7

(Rang). Additionally, biodistrubution can be altered by altering the molecule. Chemical

structures of any drugs profoundly affect both its pharmacokinetic and pharmacodynamic

properties.

Telaprevir Mechanism of Action

NS3/4A protease of HCV is an important target for the development of antiviral drugs.

NS3/4A Protease Inhibitors (PIs), telaprevir works by inhibiting protease enzymes activities in

the body. It directly interferes with the different steps of HCV life cycle by blocking the protease

enzyme that the virus must use for reproduction. The HCV NS3/4A is a multifunctional protein

that is made up of helicase domain and protease domain linked by a flexible linker (Kirkegaard).

Its activities are crucial in the production of viral nonstructural (NS) proteins which are involved

in RNA replication. Helicase activity is also required for replication of RNA. HCV useNS3/4A

protease to clip long protein strands into shorter strands that it then uses for replication. Protease

inhibitors block NS3-dependent polyprotein processing by binding to protease active sites. This

impacts other steps of the virus life cycle. Telaprevir exerts a direct effect on the synthesis of

RNA by engaging and blocking NS3 Synthesis and virus maturation (Li et al.). Additionally, it

inhibits polyprotein processing. Telaprevir rapidly inhibits production of viruses from infected

cells. The cure rate of Telaprevirtriple therapy is 75%, but it works better for certain groups than

others. The risks of long-term complications of hepatitis C such as liver cancer or needing a

liver transplant can be reduced after successful treatment.

Fig. 2: Chemical Structure of Telaprevir

Surname 8

Sofosbuvir Mechanism of Action

Nucleotide NS5B inhibitor, Sofosbuvir prevents HCV from further replicating. RNA is

key for generation of new viruses. Upon infesting the liver, HCV produces billions of virus

clones every single day. The huge magnitude of billions of virus overwhelms the immune system

reducing its ability to eliminate the viruses. Sofosbuvir blocks viral RNA polymerase which is

the component that HCV uses to construct genetic material (Maraolo). It puts on hold

multiplication of the virus thereby allowing the immune system to come in and eradicate the

viruses.

Fig. 3: Chemical Structure of Sofosbuvir

Molecular Formula: C

Sofosbuvir mechanism of action against HCV inhibits viral RNA polymerase by being a

defective substrate (Herbst Jr). It disguises itself as a nucleoside, a structural part of NS5B which

HCV uses to build new viruses. Sofosbuvir is very efficient since it is already activated and does

not require prior activation as was the case with previous antiviral drugs. Sofosbuvir mimics the

nucleoside, and attaches itself to the NS5B polymerase viral protein which is a vital component

virus replication, thus, preventing further construction of the viral protein.The number of HCV

stagnates as the immune system eliminates them resulting in healing of Hepatitis C virus

infection.

Daclatasvir Mechanism of Action

Daclatasvir (BMS790052) mechanism of action targets one of HCV proteins causing the

fastest viral decline ever seen with anti-HCV drugs. The drug is an NS5A replication complex

inhibitor that blocks two stages of the viral life cycle (Newsmedicals). The nonstructural protein

Surname 9

NS5A encoded by the HCV is a specific target for drug development. The discovery of

Daclatasvir was a huge breakthrough since the drug produced one of the most potent effects in

combating HCV with a manifold decrease in the levels of the virus within about 12 hours

(Pawlotsky). Daclatasvir blocks two distinct processes in the viral life cycle namelythe release of

the virus from the infected cells and the synthesis of new viral genomes.The drug binds to the

domain I of NS5Aprotein and blocks both virion maturation and viral replication (Marko). The

interaction of daclatasvir with the NS5A terminus causes structural distortions that interfere with

the functions of NS5A. It prevents activation and formation of the HCV replication complex.

This helps to counter the buildup of HCV in the liver thereby reducing liver damage.

Fig. 4: Chemical Structure of Daclatasvir

Molecular Formula: C

The Quantitative Structure-Activity Relationships in drugs manufacture

Many lives are lost every year due to Severe Adverse Drug Reactions (ADR). The

quantitative structure-activity relationship (QSAR) can be utilized to predict the likelihood of

drug-drug interactions (DDI) which is believed to be the cause of many deaths world over

(Alexey). QSAR is one of the earliest approach that incorporated the use of computer in

screening a large data set of small molecules and categorizing them under certain features or

descriptors. It involves the analysis of the quantitative relationship between the biological

activity of a set of compounds and their three-dimensional properties using statistical correlation

methods. QSAR makes it possible to derive compounds with elevated desired property or mix of

few. It is useful in the exploration of small molecule activities and their relation on the basis of

Surname 10

their structure relatedness. The structure relatedness between different molecules is quantified

and how similar structural parts govern their activities is searched.

QSAR of NS3/4A Protease Inhibitors Telaprevir helps to investigate the possibility of

improving biological activity of the drug (Zakharov et al.). The structure of Telaprevir is

modified, and then molecular modeling is used to calculate the QSAR properties of suggested

compounds and to select the best of the suggested compounds which are then compared with the

unmodified Telaprevir. This is useful in studying the biological activity of the new inhibitors and

the physical aspect of the interaction with the virus and selecting the possibly best compound to

synthesize (Saleh). In the study of the QSAR of Telaprevir, eleven different modifications are

suggested to the structure of Telaprevir. Molecular modeling software, SCIGRESS is then used

to carry out the calculations. The investigated compounds are built and calculations performed

with the help of SCIGRESS. Geometries optimization calculations are performed using MO-G at

the PM3 level of theory to refine the compounds' geometries. The comparison is then made

between the QSAR properties of the optimized structures and the unmodified Telaprevir. The

chemical structure of Telaprevir helps in determination of the chemical group that evokes the a

target biological effect in the organism.

Fig. 5: Chemical Structure of Telaprevir

Molecular formula: C

The suggested compounds, some QSAR, and biological activities of Telaprevir are

presented in Table II (Fig. 6: QSAR Tables). The PM3 method is used to carry out the QSAR

calculations. Dipole moment, log P and, polarizability, molar refractivity, surface area and

Surname 11

volume are QSAR descriptors used in this study. The volume and surface area of the studied

modified compound and Telaprevir are shown in Table II. The results show that the volume and

surface area values of compound number 6 are closer to that of Telaprevir than the other

compounds. The surface areas of compound number 6 and Telaprevirare 720.22 Å2 and 706.6

Å2 respectively. Molar refractivity and polarizability related to the molecule are also listed in

Table II. From the table, the molar refractivity and polarizability of compound number 6 and

Telaprevir are close to each other. The values of dipole moment are very low compared to that of

Telaprevir. Compound number 6 has the highest dipole moment. This indicates that compound

number 6 is more reactive with the biological system compared to all other compounds including

Telaprevir.

Surname 12

Fig. 6: QSAR Tables

Adopted from (Saleh).

The study of the 11 modified compounds of Telaprevir shows that compound number 6

has a remarkable biological activity ((with 1,3-dithiolane ring at position R2)) as HCV NS3

protease inhibitor and it is more stable. Compound number 6 is more reactive with biological

systems than Telaprevir. It also has a high solubility that is comparable to that of Telaprevir.

The low log P value of compound number 6 indicates that it is more hydrophilic than all of the

other modiﬁed compounds which have high log P values.

Surname 13

Works Cited

Akimitsu, Nobuyoshi. "Hepatitis C Virus NS3 Inhibitors: Current and Future Perspectives." Hindawi,

www.hindawi.com/journals/bmri/2013/467869/. Accessed 17 Aug. 2017.

Alexey, V. "QSAR Modeling and Prediction of Drug–Drug Interactions - Molecular Pharmaceutics

(ACS Publications)." ACS Publications Home Page,

pubs.acs.org/doi/full/10.1021/acs.molpharmaceut.5b00762. Accessed 17 Aug. 2017.

Fung, James. "Era of Direct Acting Antivirals in Chronic Hepatitis C: Who Will Benefit?" PubMed

Central (PMC), www.ncbi.nlm.nih.gov/pmc/articles/PMC4621468/. Accessed 17 Aug. 2017.

Graham, Brent. "Protease Inhibitors Block Multiple Functions of the NS3/4A Protease-Helicase During

the Hepatitis C Virus Life Cycle (PDF Download Available)." ResearchGate,

www.researchgate.net/publication/273155295_Protease_Inhibitors_Block_Multiple_Functions_o

f_the_NS34A_Protease-Helicase_during_the_Hepatitis_C_Virus_Life_Cycle. Accessed 17 Aug.

2017.

Herbst Jr, David Alan. "Sofosbuvir, a Nucleotide Polymerase Inhibitor, for the Treatment of Chronic

Hepatitis C Virus Infection: Expert Opinion on Investigational Drugs: Vol 22, No 4." Taylor &

Francis, www.tandfonline.com/doi/full/10.1517/13543784.2013.775246?src=recsys. Accessed

17 Aug. 2017.

Kirkegaard, K. "Protease Inhibitors Block Multiple Functions of the NS3/4A Protease-Helicase during

the Hepatitis C Virus Life Cycle." Journal of Virology, jvi.asm.org/content/89/10/5362.full.

Accessed 17 Aug. 2017.

Maraolo, AE. "The Discovery of Sofosbuvir: a Revolution for Therapy of Chronic Hepatitis C. -

PubMed - NCBI." National Center for Biotechnology Information,

www.ncbi.nlm.nih.gov/pubmed/26563720. Accessed 17 Aug. 2017.

Marko. "Sofosbuvir Mechanism of Action - How Sofosbuvir Fights of Hepatitis C Virus." Affordable

Treatment for Hepatitis C is Now Available for $1250, fixhepc.com/blog/item/41-sofosbuvir-

mechanism-of-action.html. Accessed 17 Aug. 2017.

Newsmedicals. "Daclatasvir Has Two Primary Modes of Action Against HCV." News-Medical.net,

www.news-medical.net/news/20130221/Daclatasvir-has-two-primary-modes-of-action-against-

HCV.aspx. Accessed 17 Aug. 2017.

Surname 14

Pawlotsky, Jean-Michel. "NS5A Inhibitors in the Treatment of Hepatitis C - ScienceDirect."

ScienceDirect.com | Science, Health and Medical Journals, Full Text Articles and Books,

www.sciencedirect.com/science/article/pii/S0168827813002092. Accessed 17 Aug. 2017.

Bryan-Marrugo, O.L. et al. "History and Progress of Antiviral Drugs: From Acyclovir to Direct-Acting

Antiviral Agents (Daas) For Hepatitis C." N.p., 2017. Print.

Amanda Gardner and C, Hepatitis. "This Is How Hepatitis C Is Treated (And Even Cured For Good)."

Health.com. N.p., 2017. Web. 17 Aug. 2017.

Catherine, Stedman. N.p., 2017. Web. 17 Aug. 2017.

Delang L, et al. "Hepatitis C Virus-Specific Directly Acting Antiviral Drugs. - Pubmed - NCBI."

Ncbi.nlm.nih.gov. N.p., 2017. Web. 17 Aug. 2017.

Halfon, C. "Future Treatment of Chronic Hepatitis C with Direct Acting Antivirals: Is Resistance

Important? - Pubmed - NCBI." Ncbi.nlm.nih.gov. N.p., 2017. Web. 17 Aug. 2017.

hepctip.ca/daas/. "The Four Classes of Hep C Treatment Daas." Hepatitis C Treatment Information

Project. N.p., 2017. Web. 17 Aug. 2017.

http://www.hepatitisc.uw.edu/. "Hepatitis C Online." Hepatitisc.uw.edu. N.p., 2017. Web. 17 Aug. 2017.

NCBI https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5225151/. "Hepatitis C Virus: A Review of

Treatment Guidelines, Cost-Effectiveness, and Access to Therapy." N.p., 2017. Print.

Jakobsen, Janus C et al. "Direct-Acting Antivirals for Chronic Hepatitis C." N.p., 2017. Print.

K, Gane. "Directly Acting Antivirals (Daas) For the Treatment of Chronic Hepatitis C Virus Infection in

Liver Transplant Patients: "A Flood of Opportunity". - Pubmed - NCBI." Ncbi.nlm.nih.gov. N.p.,

2017. Web. 16 Aug. 2017.

Li, You et al. "The Yin and Yang of Hepatitis C: Synthesis and Decay of Hepatitis C Virus RNA." N.p.,

2017. Print.

Lin, Chao. "HCV NS3-4A Serine Protease." Ncbi.nlm.nih.gov. N.p., 2017. Web. 17 Aug. 2017.

medicaleconomics. "Daas Aid Treatment of Hepatitis C Patients with Cancer." Medical Economics.

N.p., 2017. Web. 17 Aug. 2017.

Saleh, Noha A. Saleh. N.p., 2017. Web. 16 Aug. 2017

Strader, Doris B., and Leonard B. Seeff. "A Brief History of the Treatment of Viral Hepatitis C." N.p.,

2017. Print.

WHO 2017. "Key Facts on Hepatitis C Treatment." World Health Organization. N.p., 2017. Web. 17

Aug. 2017.

Surname 15

Zakharov, Alexey V. et al. "QSAR Modeling and Prediction of Drug–Drug Interactions." N.p., 2017.

Print.

Zappulo, Emanuela. "The Discovery of Sofosbuvir: A Revolution for Therapy of Chronic Hepatitis C."

Taylor & Francis. N.p., 2017. Web. 17 Aug. 2017.

Rosenquist, Asa. "Discovery and Development of Simeprevir (TMC435), a HCV NS3/4A Protease

Inhibitor Journal of Medicinal Chemistry (ACS Publications)."

pubs.acs.org/doi/abs/10.1021/jm401507s. Accessed 18 Aug. 2017.

Clercq E, De. "Current Race in the Development of DAAs (direct-acting Antivirals) Against HCV. -

PubMed - NCBI." National Center for Biotechnology Information,

www.ncbi.nlm.nih.gov/pubmed/24735613. Accessed 18 Aug. 2017.

Mehnaz, Kamal. "STEREOCHEMISTRY AND ITS ROLE IN DRUG DESIGN | INTERNATIONAL

JOURNAL OF PHARMACEUTICAL SCIENCES AND RESEARCH." International Journal of

Pharmaceutical Sciences and Research (IJPSR), ijpsr.com/bft-article/stereochemistry-and-its-

role-in-drug-design/?view=fulltext. Accessed 18 Aug. 2017.

Rang, H. P. "The Receptor Concept: Pharmacology's Big Idea." PubMed Central (PMC),

www.ncbi.nlm.nih.gov/pmc/articles/PMC1760743/. Accessed 18 Aug. 2017.

Place new order. It's free, fast and safe

Paper type

Deadline

Page count

550 words

Total price: $ 15.00

Our customers say

Jeff Curtis

USA, Student

"I'm fully satisfied with the essay I've just received. When I read it, I felt like it was exactly what I wanted to say, but couldn’t find the necessary words. Thank you!"

Ian McGregor

UK, Student

"I don’t know what I would do without your assistance! With your help, I met my deadline just in time and the work was very professional. I will be back in several days with another assignment!"

Shannon Williams

Canada, Student

"It was the perfect experience! I enjoyed working with my writer, he delivered my work on time and followed all the guidelines about the referencing and contents."