Anti HIV Drugs. Non-Nucleoside Reverse Transcriptase Inhibitors

NNRTIs as Anti HIV Drugs


Literature Review, 2014
65 Pages

Excerpt

Table of Contents

Preface

Acknowledgements

List of Figures

List of Tables

List of Abbreviations

Chapter– 1: History

Chapter‒ 2: HIV Virus
2.1 Structure of HIV
2.2 HIV Life Cycle
2.2.1 Entry or Binding and Fusion
2.2.2 Reverse Transcription (RT)
2.2.3 Integration (IN)
2.2.4 Transcription
2.2.5 Assembly
2.2.6 Budding
2.2.7 Maturation

Chapter‒ 3: Anti HIV Drugs
3.1 Classification of Anti HIV Drugs
3.1.1 Entry Inhibitors
3.1.2 Integrase Inhibitors
3.1.3 Nucleoside (NRTI) and Nucleotide (NtRTIs) Reverse Transcriptase Inhibitors
3.1.4 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
3.1.5 Protease Inhibitors (PIs)
3.2 FDA approved Anti HIV Drugs

Chapter‒ 4: Non-Nucleoside Reverse Transcriptase Inhibitors
4.1 HIV Reverse Transcriptase (RT) enzyme
4.2 Mechanism of action of NNRTIs

Chapter‒ 5: Important classes of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
5.1 TIBO {4,5,6,7-Tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepine-2(1H)-ones} derivatives
5.2 HEPT {1-[(2-hydroxyethoxy) methyl]-6-(phenylthio) thymine}
5.3 Pyridinones
5.4 Thiocarboxanilide derivatives
5.5 DABO {Dihydroalkoxybenzyloxopyrimidine}
5.6 DATA {Diaryl triazine}
5.7 DAPYs {Diarylpyrimidines}
5.8 PBOs {Pyrrolobenzoxazepinones}
5.9 Benzoxazinones
5.10 2- Amino pyrimidine
5.11 Benzophenone
5.12 α-Anilinophenylacetamides (α-APAs)
5.13 Dipyridodiazepinones
5.14 PETT {Phenyl Ethyl Thiourea Thiazole}
5.15 BHAP {Bis (heteroaryl)-Piperazine} derivatives

Chapter‒ 6: HIV and drug resistance

Chapter‒ 7: Highly Active Antiretroviral Therapy

Chapter‒ 8: Conclusion

References

Preface

The proposed book entitled, “Anti HIV Drugs: Non-Nucleoside Reverse Transcriptase Inhibitors” gives an outline of the Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI) class of Anti HIV drugs, from the initial discovery of the class in 1990 to the current compounds in clinical development, i.e. around 20 years of research and development efforts. It describes the characteristics of the NNRTIs, their mechanisms of action, HIV resistance to the inhibitors, and the drugs that have been approved for the treatment of HIV infection, that are currently in clinical development. The role of NNRTIs in prevention of HIV transmission is also addressed. The book also covers some basic information about HIV, AIDS and HIV life cycle.

ACKNOWLEDGEMENTS

This Book would not have been possible without the guidance and the help of several individuals who in one way or another contributed and extended their valuable assistance in the preparation and completion of this study. It is a pleasure to convey my gratitude to them all in my humble acknowledgment.

I convey my heartfelt thanks to Director, Sardar Vallabhbhai National Institute of Technology, Surat for providing me all the required facilities and financial assistance to carry out my research work.

It is a pleasure to express my sincere gratitude to HVHP Institute of Postgraduate Studies and Research and Kadi Sarva Vishwavidyalaya for providing a wonderful working environment. There are no proper words to convey my deep gratitude and respect to Dr. Hasit Dangi, whom I was fortunate to meet when he was holding an honorary Senior Manager’s position at Bayer Crop Science. He has inspired me to become an independent researcher and helped me realize the power of critical reasoning.

A journey is easier when you travel together. Interdependence is certainly more valuable than independence. This book is the result of love from my wife Vibhu, who was always there when I really needed. Thank you doesn’t seem sufficient but it is said with appreciation and respect for her support, encouragement, care, understanding and precious friendship. My son Avi owed a debt of gratitude by me for sacrificing playtime while his father typed away in the basement. This helped me a lot to work for hours together tirelessly. During my research work there was continues support from my family. It was their kindness and patience that they allowed my absence from my family duties. I have no words to express my gratitude for the unconditional love, support, inspiration and blessings given by my father Shri Babubhai F. Mahyavanshi and my mother Smt. Chanchalben B. Mahyavanshi.

Besides this, several people have knowingly and unknowingly helped me in the successful completion of this book. I doubt that I will ever be able to convey my appreciation fully, but I owe such people my eternal gratitude.

List of Figures

Figure 1.1Global prevalence of HIV, 2009

Figure 2.1Schematic of the HIV virus

Figure 2.2HIV life cycle

Figure 3.1Structural formulae of NRTIs and the NtRTI

Figure 3.2Structural formula of the pyrophosphate analogue foscarnet

Figure 4.1Mode of action of NNRTIs

Figure 4.2Diagram comparing the NNRTI site and polymerase active site in Reverse Transcriptase

List of Tables

Table 3.2.1Fusion Inhibitors

Table 3.2.2Entry Inhibitors - CCR5 co-receptor antagonist

Table 3.2.3HIV integrase strand transfer inhibitors

Table 3.2.4Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Table 3.2.5Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Table 3.2.6Protease Inhibitors (PIs)

Table 3.2.7Multi-class Combination Products

List of Abbreviations

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1.0. History

In 1983, Françoise Barre-Sinoussi had identified Human Immunodeficiency Virus and proved this virus causes AIDS. HIV is a retrovirus. HIV attacks the body's immune system. Normally, the immune system produces white blood cells and antibodies that attack viruses and bacteria. The infection fighting cells are called T-cell lymphocytes. Months to years after a person is infected with HIV, the virus destroys all the T-cell lymphocytes. This disables the immune system to defend the body against diseases and tumors. Various infections will be able to develop; these opportunistic infections take advantage of the body's weakened immune system. These infection which normally won't cause severe or fatal health problems will eventually cause the death of the HIV patient. [1]

AIDS stands for Acquired Immuno Deficiency Syndrome. It is a disease in which the body’s immune system breaks down and is unable to fight off infections, known as "opportunistic infections," and other illnesses that take advantage of a weakened immune system. When a person is infected with HIV, the virus enters the body and lives and multiplies primarily in the white blood cells. These are immune cells that normally protect us from disease. The hallmark of HIV infection is the progressive loss of a specific type of immune cell called T-helper or CD4 cells. As the virus grows, it damages or kills these and other cells, weakening the immune system and leaving the person vulnerable to various opportunistic infections and other illnesses ranging from pneumonia to cancer. In some people, the T-cell decline and opportunistic infections that signal AIDS develop soon after infection with HIV. But most people do not develop symptoms for 10 to 12 years. [1][2]

Since the beginning of the epidemic, almost 60 million people have been infected with HIV and 25 million people have died of HIV related causes. In 2008, some 33.4 million [31.1 million-35.8 million] people living with HIV, 2.7 million [2.4 million-3.0 million] new infections and 2 million [1.7 million-2.4 million] AIDS related deaths. Young people account for around 40% of all new adult (15+) HIV infections worldwide. Sub-Saharan Africa is the region most affected and is home to 67% of all people living with HIV worldwide and 91% of all new infections among children. In sub-Saharan Africa the epidemic has orphaned more than 14 million children. [3]

The human immunodeficiency virus type 1 (HIV-1) was discovered in 1983 as the primary causative agent of the acquired immunodeficiency syndrome (AIDS). It was first called lymphadenopathy-associated virus [4], later human T cell lymphotropic virus type III [5], and AIDS related virus [6]. Although there was a rather high diversity in the envelope-coding gene [7], electron microscopy and comparison of the genome sequences of the three isolates showed very high homology and relationship with lentiviruses, genus of the retroviridae [8]. In 1986 they were all given the name HIV-1. In 1985, a second antigenic variant, designated HIV-2, was isolated from an AIDS patient in West Africa [9]. Both HIV-1 and HIV-2 are the result of an interspecies transmission of simian immunodeficiency virus (SIV) from chimpanzees and sooty mangabeys [10] to humans, respectively. HIV-2 shares approximately 60% nucleotide sequence similarity with HIV-1 and is primarily found in West Africa, while HIV-1 has spread globally.

In Asia, as shown in Figure 1.1, national HIV prevalence is highest in South-East Asia, with wide variation in epidemic trends between different countries. UNAIDS estimates that there were 33.3 million [31.4 million–35.3 million] people living with HIV at the end of 2009 compared with 26.2 million [24.6 million– 27.8 million] in 1999—a 27% increase. Although the annual number of new HIV infections has been steadily declining since the late 1990s, this decrease is offset by the reduction in AIDS-related deaths due to the significant scale up of antiretroviral therapy over the past few years.

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Figure 1.1 Global prevalence of HIV, 2009

Source: UNAIDS (www.unaids.org)

The impact of the infection in the developing countries is dramatic because it disrupts the complete social structure by affecting a large part of the working population and because it leaves behind a large number of orphans. It is clear that the epidemic in the developing world is more problematic than in the western world, where the disease is better controlled due to availability of antiretroviral chemotherapy and numerous prevention campaigns. Unfortunately, due to the overall access to different antiviral drugs in the western world, there is complacency about the risks of HIV and safe sex behavior is being eroded. Overall, early diagnosis and prevention should remain of highest priority to overcome new infections and development of new antiviral drugs and effective HIV vaccines are important to stop the expansion of the epidemic.

2.0. HIV Virus

The unicellular microorganism (like bacteria) however small and simple, are cells. Unicellular microorganisms always contain DNA as the repository of genetic information, and in addition, also RNA. These cells have their own machinery for producing energy and macromolecules. Thus, the unicellular microorganisms grow by synthesizing their own macromolecular constituents (nucleic acids, proteins, carbohydrates, and lipids), and in the majority of cases, multiply by binary fission.

Viruses, on the other hand, are not cells. They are completely dependent on their cellular hosts for the machinery of energy production and synthesis of macromolecules. The virus particle contains only one type of nucleic acid, either DNA or RNA, never both, and differs from non-viral organisms by having two clearly defined phases in their life cycle. In the first phase (the transmission phase) outside a susceptible cell, the virus particle is metabolically inert. In the second phase (the reproductive phase) inside the cell, the viral genome exploits the metabolic pathways of the host to produce progeny genomes and viral proteins that assemble to form new infectious virus particles called virions [11]. The primary target of HIV seems to be CD4+ T lymphocytes which are part of the machinery of our immune system [12].

2.1. Structure of HIV

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Figure 2.1 Schematic of the HIV virus

The primary phase of HIV infection progresses fairly rapidly and may exhibit mononucleosis-like symptoms within a few weeks [13]. During this early phase, the extent of infection is high and virion (virus particle) concentration may exceed a million copies per mL of blood [14]. The structure of HIV virus is displayed in the Figure 2.1. The host's immune response usually kicks in after a few weeks and the level of virus in the blood declines to bring HIV infection into its second phase. This long, asymptomatic period characterizes HIV as a lentivirus ("slow virus") [15]. Viral replication is still active and cells are rapidly being infected and eliminated during this period [16, 17]. The turnover of T cells gradually leads to a decline in their number [18]. In the third and final phase of infection, the number of CD4+ cells drops more quickly and the viral load increases to produce clinical immunodeficiency. A schematic representation of the replication cycle of HIV appears in Figure 2.2.

2.2. HIV Life Cycle: [19, 20]

HIV can infect multiple cells in our body, including brain cells, but its main target is the CD4 lymphocyte, also called a T-cell or CD4 cell. When a CD4 cell is infected with HIV, the virus goes through multiple steps to reproduce itself and create many more virus particles.

The process is broken up into the following steps:

2.2.1. Entry or Binding and Fusion

HIV begins to enter a CD4 cell by binding itself to specific point called a CD4 receptor. After Binding and fusion, HIV release RNA and enzymes in to CD4 cell. HIV uses a receptor on its surface called gp120 (glycoprotein 120, akaenvelope protein) to bind to CD4 cells. The receptors on CD4 cells that gp120 interacts with are CD4 and one of two chemokine co-receptors, CXCR4 or CCR5. Once bound to the cell surface, a conformational change in the receptors allows the virus to enter the cell.

2.2.2. Reverse Transcription (RT)

In this stage HIV’s RNA changes in to DNA. An HIV enzyme called Reverse transcriptase changes HIV RNA in to HIV DNA. Once the HIV is in the host cell, the virus protective covering (nucleocapsid) degrades and releases the two RNA strands that comprise the HIV genome. The HIV genome is converted from RNA to dsDNA by the enzymatic action of Reverse Transcriptase.

2.2.3. Integration (IN)

The copy of the HIV genome in DNA form is inserted into the host's genome by the enzymatic action of integrase. Once inserted into the host genome, HIV is called a provirus. The HIV genome, which encodes for HIV proteins, is translated by host cell machinery into immature or nascent polypeptides that have no function until cleaved into smaller polypeptides.

2.2.4. Transcription

This step is transcription of proviral DNA in to viral RNA. This RNA is then translating in to viral protein. The proteins are the building blocks for new HIV viruses. They are produced in long chains.

2.2.5. Assembly

An enzyme called Protease cuts the long chains of HIV proteins in to smaller pieces. As the smaller protein pieces come together and develop capsid for new viral. The two single standard RNA, all three enzymes and protein capsid come together and assembled a new virus.

2.2.6. Budding

The newly-assembled virus pushes out of the original CD4 cell. During budding, the new virus steals part of the cell's outer envelope. This envelope, which acts as a covering, is studded with protein/sugar combinations called HIV glycoprotein.

2.2.7. Maturation

In this step viral develops its own envelop. The newly matured HIV particles are ready to infect another cell and begin the replication process all over again. In this way the virus spreads through the human body.

And once a person is infected, they can pass on to others in their body fluids. Figure 2.2 shows the HIV life cycle.

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Figure-2.2 HIV life cycle

3.0. Anti HIV Drugs

Anti HIV drugs are also known as Antiretroviral drugs. Antiretroviral therapy of HIV infection has changed a uniformly fatal into a potentially chronic disease. There are now 17 drugs in common use for HIV treatment. Patients who can access and adhere to combination therapy should be able to achieve durable, potentially lifelong suppression of HIV replication.

Despite the unquestioned success of Antiretroviral therapy, limitations persist. Treatment success needs strict lifelong drug adherence. Although the widely used drugs are generally well tolerated, most have some short-term toxic effects and all have the potential for both known and unknown long-term toxic effects. Drug and administration costs limit treatment in resource-poor regions, and are a growing concern even in resource rich settings. Finally, complete or near complete control of viral replication does not fully restore health. Long-term treated patients who are on an otherwise effective regimen often show persistent immune dysfunction and have higher than expected risk for various non-AIDS-related complications, including heart, bone, liver, kidney, and neurocognitive diseases. Anti HIV drugs target the different steps of the virus life cycle. [21]

3.1. Classification of Anti HIV Drugs [22]

According to HIV life cycle, Anti HIV drugs are classified in to following different groups.

3.1.1. Entry Inhibitors

They are divided in to two different parts, Fusion inhibitors and CCR5 antagonist. Fusion inhibitors are essentially to head the virus off at the pass, attacking it before it gets a chance to attack the body. CCR5 antagonist binding alters the conformational state of the CCR5 receptor, inhibiting the binding of gp120 to CCR5 by an allosteric mechanism.

3.1.2. Integrase Inhibitors

One of the critical steps in the HIV life cycle is the integration of the virus's genetic information into the host cell DNA. This allows the host cell to turn into a "HIV factory" and produce many, many virion each hour. The enzyme Integrase is the enzyme that accomplishes this task. Integrase inhibitors serve to stop this enzyme.

3.1.3. Nucleoside (NRTI) and Nucleotide (NtRTIs) Reverse Transcriptase Inhibitors

Nucleoside/Nucleotide reverse transcriptase inhibitors (NRTIs) were the first HIV medications to be discovered. They have been considered the “backbone” of all Antiretroviral regimens. They are convenient pills and have few drug interactions. The prototype of this class is Zidovudine, which has been known to reach the CNS better than any other ART drug. These drugs interfere with HIV’s reverse Transcriptase enzyme. NRTIs and NtRTIs are chain terminators. They are incorporated into the nascent chain of viral DNA. Because they lack a 3'-hydroxyl group, no additional nucleotides can be appended.

The NtRTIs, such as adefovir (PMEA) and tenofovir ((R)-PMPA) can be considered as NRTIs that have an intact nucleobase part but an acyclic sugar (aliphatic) part equipped with a phosphonate (P-C) bond. This circumvents the problem of the initial, limiting phosphorylation step that NRTIs have to encounter. NtRTIs are also further phosphorylated by cellular kinases to the corresponding mono- and diphosphates and act, like NRTIs, as DNA chain terminators of nascent viral DNA synthesis. The structural formulae of some important NRTIs and the NtRTI are displayed in the Figure 3.1.

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Figure 3.1. Structural formulae of NRTIs and the NtRTI

3.1.4. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

A second class of ART that also inhibits reverse transcriptase is called NNRTI. Like NRTIs, these drugs interfere with HIV’s reverse transcriptase enzyme. They bind to an active site on reverse transcriptase, directly inhibiting it. Non Nucleoside Reverse Transcriptase Inhibitors are Small molecules with strong affinity for a hydrophobic pocket located near the catalytic domain of RT. Inhibitor binding affects the flexibility of the enzyme, thereby blocking its ability to synthesize DNA.

[...]

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Details

Title
Anti HIV Drugs. Non-Nucleoside Reverse Transcriptase Inhibitors
Subtitle
NNRTIs as Anti HIV Drugs
Author
Year
2014
Pages
65
Catalog Number
V283092
ISBN (eBook)
9783656831815
ISBN (Book)
9783656830849
File size
1936 KB
Language
English
Tags
anti, drugs, non-nucleoside, reverse, transcriptase, inhibitors, nnrtis
Quote paper
Amit Patel (Author), 2014, Anti HIV Drugs. Non-Nucleoside Reverse Transcriptase Inhibitors, Munich, GRIN Verlag, https://www.grin.com/document/283092

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