423
there are 20,000 genes and around 100,000 proteins in humans; among these, only
324 targets resulted in approved drugs (Mayr and Bojanic 2009). Of these, only 266
are human genome-derived proteins, the rest are microbial targets. Despite the
potential profits and the extraordinary capacity of drug discovery technology, there
is a scarcity of new drugs in the development pipeline, particularly for those medications that are likely to be highly profitable because they are used long term and by
a large proportion of the population. Validation techniques range from in vitro tools
through the use of whole animal models, to modulation of desired target in patients.
While each approach is valid in its own right, confidence in the observed outcome
is significantly increased by a multivalidation approach (Fig. 18.2).
Development of antiviral drugs is a very lengthy process as it involves many
stages such as target identification and screening (Table 18.1), lead generation and
optimization, preclinical and clinical studies, and final registration of the drug
(Fig. 18.1). Increasing knowledge about viruses, mechanism of their infections, and
the rapid evolvement of novel antiviral strategies and techniques will speed up the
development of novel antiviral drugs. Here we emphasize one such advancement
toward the development of HIV-AIDS therapeutics.
18.2 HIV Life Cycle in a Nutshell
18.2.1 Functions and Targets
In the last three decades, a number of efforts have led to better understanding of
the virus life cycle and design of therapeutics for its control. The primary targets
of the HIV virus are CD
+
T cells, monocytes, macrophages, and dendritic cells
(Ramana et al. 2014). The decrease in the number of CD
+
T cells leads to failure
of the immune response system, which eventually leads to fatality. From the point
of entry into the human T cells, a number of processes are required for virus maturation. Each of the important stages of the viral maturation serves as a target for
potential development of AIDS therapeutics. At present, there are about 30 FDAapproved (Table 18.2, Fig. 18.3) drugs of five different classes that are part of
highly active antiretroviral therapy (HAART) (Zhan et al. 2016).
After the HIV infection, which is contracted via three major routes – sexual transmission, blood transfusion, and by passage from mother to child – seven key steps
determine the life cycle of the virus, which are as follows: (1) binding, (2) fusion, (3)
reverse transcription, (4) integration, (5) replication, (6) assembly, and (7) budding.
The HIV virus begins its life cycle by binding to CD4 receptor cells of the host.
This binding is initiated by glycoprotein gp120 on the outer envelope of HIV and is
promoted by chemokine receptors CCR5/CXCR4. The binding of gp120 to CD4
receptor leads to conformational changes in gp120, which promotes gp41-mediated
fusion of the virus particle to the host cell (O’Hara and Olson 2002). The fusion is
followed by release of HIV capsid which contains HIV RNA and three key enzymes,
reverse transcriptase, integrase, and protease, that are essential to virus life and its
proliferation. At this stage, within CD4 membrane, HIV capsid releases HIV RNA,
which undergoes reverse transcription to make HIV DNA. The newly formed HIV
18 Novel Targets and Advancements in Drug Discovery: The Case of HIV-AIDS
there are 20,000 genes and around 100,000 proteins in humans; among these, only
324 targets resulted in approved drugs (Mayr and Bojanic 2009). Of these, only 266
are human genome-derived proteins, the rest are microbial targets. Despite the
potential profits and the extraordinary capacity of drug discovery technology, there
is a scarcity of new drugs in the development pipeline, particularly for those medications that are likely to be highly profitable because they are used long term and by
a large proportion of the population. Validation techniques range from in vitro tools
through the use of whole animal models, to modulation of desired target in patients.
While each approach is valid in its own right, confidence in the observed outcome
is significantly increased by a multivalidation approach (Fig. 18.2).
Development of antiviral drugs is a very lengthy process as it involves many
stages such as target identification and screening (Table 18.1), lead generation and
optimization, preclinical and clinical studies, and final registration of the drug
(Fig. 18.1). Increasing knowledge about viruses, mechanism of their infections, and
the rapid evolvement of novel antiviral strategies and techniques will speed up the
development of novel antiviral drugs. Here we emphasize one such advancement
toward the development of HIV-AIDS therapeutics.
18.2 HIV Life Cycle in a Nutshell
18.2.1 Functions and Targets
In the last three decades, a number of efforts have led to better understanding of
the virus life cycle and design of therapeutics for its control. The primary targets
of the HIV virus are CD
+
T cells, monocytes, macrophages, and dendritic cells
(Ramana et al. 2014). The decrease in the number of CD
+
T cells leads to failure
of the immune response system, which eventually leads to fatality. From the point
of entry into the human T cells, a number of processes are required for virus maturation. Each of the important stages of the viral maturation serves as a target for
potential development of AIDS therapeutics. At present, there are about 30 FDAapproved (Table 18.2, Fig. 18.3) drugs of five different classes that are part of
highly active antiretroviral therapy (HAART) (Zhan et al. 2016).
After the HIV infection, which is contracted via three major routes – sexual transmission, blood transfusion, and by passage from mother to child – seven key steps
determine the life cycle of the virus, which are as follows: (1) binding, (2) fusion, (3)
reverse transcription, (4) integration, (5) replication, (6) assembly, and (7) budding.
The HIV virus begins its life cycle by binding to CD4 receptor cells of the host.
This binding is initiated by glycoprotein gp120 on the outer envelope of HIV and is
promoted by chemokine receptors CCR5/CXCR4. The binding of gp120 to CD4
receptor leads to conformational changes in gp120, which promotes gp41-mediated
fusion of the virus particle to the host cell (O’Hara and Olson 2002). The fusion is
followed by release of HIV capsid which contains HIV RNA and three key enzymes,
reverse transcriptase, integrase, and protease, that are essential to virus life and its
proliferation. At this stage, within CD4 membrane, HIV capsid releases HIV RNA,
which undergoes reverse transcription to make HIV DNA. The newly formed HIV
18 Novel Targets and Advancements in Drug Discovery: The Case of HIV-AIDS