428
DNA then passes through the CD4 nuclear membrane where it undergoes integration with the host cell DNA facilitated by the enzyme integrase. Using this machinery, the proviral DNA hides itself within the host cell DNA and leads to the
higher-latency period of the virus. Within the host nucleus, the proviral DNA undergoes routine steps of transcription and translation to make new HIV viral proteins.
The final stage of the virus life cycle is assembly and maturation of the new HIV
RNA where the RNA and proteins exit out of the host cell membrane during which
they remain noninfectious. The long chains of polypeptides then get broken down
into smaller fragments of proteins by proteases and finally get processed as infectious viral particles at the maturation stage.
All seven important steps of the HIV virus life cycle have been envisaged as
potential targets for developing therapy. A number of advances toward inhibition of
these processes have led to the development of HAART and other agents of chemotherapy which have curtailed virus proliferation and enhanced life expectancy. Here
we list therapeutic advances made toward HIV therapy and highlight some of the
current drug discovery approaches. Traditionally, discovery approaches have
screened a large number of drug-like molecules, often using high-throughput assays
to identify lead compounds and subsequently perform structure-based modifications to enhance their efficacy. But several new screening approaches have identified novel structural motifs for AIDS therapy. For example, fragment-based
screening has led to the identification of molecules containing indole core as protease inhibitors. This work led to subsequent discovery of brominated benzoic and
naphthoic acid derivatives as new protease inhibitors. These discoveries demonstrate that fragment-based design of new molecules can provide complementary
approaches to established drug discovery screening essays. A number of other
approaches such as privileged fragment-based reconstruction approach, dynamic
ligation scattering, rapid diversity-oriented and in situ screening, and hierarchical
virtual screening are in practice to supplement traditional methods of drug discovery (Ghosh et al. 2016).
18.3 Advances in the HIV Drug Development
Despite the progress in antiretroviral therapy, the significantly high mutation rate of
the HIV virus has mandated newer alternatives to currently used drugs not just to
have a different line of therapeutics but also to discover more efficacious drugs.
Here we outline recent advances made toward inhibition of seven key steps required
for virus life cycle.
18.3.1 Entry Inhibitors
The enveloped HIV virus undergoes cell surface fusion with the CD4 cells as the
first step of its entry to the host cell. The virion is surrounded by a cell-surface glycoprotein gp120 and a transmembrane glycoprotein gp41, both of which can act as
N. Ranjan et al.
DNA then passes through the CD4 nuclear membrane where it undergoes integration with the host cell DNA facilitated by the enzyme integrase. Using this machinery, the proviral DNA hides itself within the host cell DNA and leads to the
higher-latency period of the virus. Within the host nucleus, the proviral DNA undergoes routine steps of transcription and translation to make new HIV viral proteins.
The final stage of the virus life cycle is assembly and maturation of the new HIV
RNA where the RNA and proteins exit out of the host cell membrane during which
they remain noninfectious. The long chains of polypeptides then get broken down
into smaller fragments of proteins by proteases and finally get processed as infectious viral particles at the maturation stage.
All seven important steps of the HIV virus life cycle have been envisaged as
potential targets for developing therapy. A number of advances toward inhibition of
these processes have led to the development of HAART and other agents of chemotherapy which have curtailed virus proliferation and enhanced life expectancy. Here
we list therapeutic advances made toward HIV therapy and highlight some of the
current drug discovery approaches. Traditionally, discovery approaches have
screened a large number of drug-like molecules, often using high-throughput assays
to identify lead compounds and subsequently perform structure-based modifications to enhance their efficacy. But several new screening approaches have identified novel structural motifs for AIDS therapy. For example, fragment-based
screening has led to the identification of molecules containing indole core as protease inhibitors. This work led to subsequent discovery of brominated benzoic and
naphthoic acid derivatives as new protease inhibitors. These discoveries demonstrate that fragment-based design of new molecules can provide complementary
approaches to established drug discovery screening essays. A number of other
approaches such as privileged fragment-based reconstruction approach, dynamic
ligation scattering, rapid diversity-oriented and in situ screening, and hierarchical
virtual screening are in practice to supplement traditional methods of drug discovery (Ghosh et al. 2016).
18.3 Advances in the HIV Drug Development
Despite the progress in antiretroviral therapy, the significantly high mutation rate of
the HIV virus has mandated newer alternatives to currently used drugs not just to
have a different line of therapeutics but also to discover more efficacious drugs.
Here we outline recent advances made toward inhibition of seven key steps required
for virus life cycle.
18.3.1 Entry Inhibitors
The enveloped HIV virus undergoes cell surface fusion with the CD4 cells as the
first step of its entry to the host cell. The virion is surrounded by a cell-surface glycoprotein gp120 and a transmembrane glycoprotein gp41, both of which can act as
N. Ranjan et al.