430
18.3.2 Reverse Transcriptase Inhibitors
Once the virus enters the cytoplasm of the host cell, the reverse transcriptase (RT)
of the virus is activated. In addition to other assisting cellular factors, RT performs
reverse transcription reactions using DNA polymerase and RNase H to make new
copies of double-stranded DNA. The reverse transcription process begins with the
binding of the tRNA primer to the 5′ end of viral RNA known as the primer binding
site. The initiated minus-strand DNA synthesis is transferred to the 3′ end of either
of the two copies of viral RNA, which is released from the capsid in the host cell
cytoplasm. The minus-strand DNA synthesis is continued along with RNase H degradation. A polypurine tract in the RNA resists RNA degradation and ultimately
serves as the template for plus-strand DNA synthesis. The plus-strand DNA synthesis also generates 18 nucleotides for the tRNA primer.
Inhibiting HIV RT activity has been one of the most sought after targets in HIV
therapy. Of currently approved FDA drugs for HIV therapy, nearly half of them
belong to the class of RT inhibitors. In fact, the very first anti-HIV drug, azidothymidine (AZT), belonged to the class of RT inhibitors. The RT inhibitors have been
classified into two main classes (Table 18.2): nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). NRTIs
act as mimics of natural substrates of DNA synthesis. The sugar moiety of the
nucleoside analogs lacks the 3′-OH functionality which is catalytically essential.
Once these nucleoside mimics are incorporated inside the cells, they are converted
as their triphosphate analogs by cellular enzymes (kinases) to be active. The triphosphate analogs thus produced are used by RT for making DNA, which, in turn, acts
as chain terminators blocking the DNA synthesis. On the other hand, NNRTIs act
by a non-competing mechanism where they induce allosteric conformational
changes to the catalytic activity of the enzyme.
The success of AZT led to research focus on the development of NRTIs, which
resulted in a few more FDA drugs such as Stavudine and Lamivudine by the mid1990s which acted by mimicking natural nucleoside substrate thymidine triphosphate. But soon viral resistance necessitated alternatives, which resulted in the
development of NNRTIs with Nevirapine being the first FDA-approved drug in this
class. Several new molecules have been reported with excellent activity and promise
(Fig. 18.5). From a large sample size (over 20,000 compounds) and using highthroughput assay, novel phenylaminopyridine derivatives (Fig. 18.5(7)) were identified as NNRTIs with low nanomolar inhibitory concentrations against RT activity
(Kim et al. 2012). Using a molecular hybridization strategy, 6-substituted diarylpyridine derivatives (Fig. 18.5(8)) have been designed which show more potent
activities than Nevirapine (Yang et al. 2016). RT-related RNase H activity has also
been targeted recently with reasonable cell-based antiviral activity using hydroxypyridonecarboxylic acid derivatives (Fig. 18.5(9)) (Kankanala et al. 2016). Compounds
containing the Imidazole-amide biaryl scaffold (Fig. 18.5(10)) have also shown
good overall RT activity, which promises a new class of alternative compounds
(Chong et al. 2012). Molecular simulation-based design of pyrimidine sulfonylacetanalides (Fig. 18.5(11)) has shown very good activity against clinically relevant
N. Ranjan et al.
18.3.2 Reverse Transcriptase Inhibitors
Once the virus enters the cytoplasm of the host cell, the reverse transcriptase (RT)
of the virus is activated. In addition to other assisting cellular factors, RT performs
reverse transcription reactions using DNA polymerase and RNase H to make new
copies of double-stranded DNA. The reverse transcription process begins with the
binding of the tRNA primer to the 5′ end of viral RNA known as the primer binding
site. The initiated minus-strand DNA synthesis is transferred to the 3′ end of either
of the two copies of viral RNA, which is released from the capsid in the host cell
cytoplasm. The minus-strand DNA synthesis is continued along with RNase H degradation. A polypurine tract in the RNA resists RNA degradation and ultimately
serves as the template for plus-strand DNA synthesis. The plus-strand DNA synthesis also generates 18 nucleotides for the tRNA primer.
Inhibiting HIV RT activity has been one of the most sought after targets in HIV
therapy. Of currently approved FDA drugs for HIV therapy, nearly half of them
belong to the class of RT inhibitors. In fact, the very first anti-HIV drug, azidothymidine (AZT), belonged to the class of RT inhibitors. The RT inhibitors have been
classified into two main classes (Table 18.2): nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). NRTIs
act as mimics of natural substrates of DNA synthesis. The sugar moiety of the
nucleoside analogs lacks the 3′-OH functionality which is catalytically essential.
Once these nucleoside mimics are incorporated inside the cells, they are converted
as their triphosphate analogs by cellular enzymes (kinases) to be active. The triphosphate analogs thus produced are used by RT for making DNA, which, in turn, acts
as chain terminators blocking the DNA synthesis. On the other hand, NNRTIs act
by a non-competing mechanism where they induce allosteric conformational
changes to the catalytic activity of the enzyme.
The success of AZT led to research focus on the development of NRTIs, which
resulted in a few more FDA drugs such as Stavudine and Lamivudine by the mid1990s which acted by mimicking natural nucleoside substrate thymidine triphosphate. But soon viral resistance necessitated alternatives, which resulted in the
development of NNRTIs with Nevirapine being the first FDA-approved drug in this
class. Several new molecules have been reported with excellent activity and promise
(Fig. 18.5). From a large sample size (over 20,000 compounds) and using highthroughput assay, novel phenylaminopyridine derivatives (Fig. 18.5(7)) were identified as NNRTIs with low nanomolar inhibitory concentrations against RT activity
(Kim et al. 2012). Using a molecular hybridization strategy, 6-substituted diarylpyridine derivatives (Fig. 18.5(8)) have been designed which show more potent
activities than Nevirapine (Yang et al. 2016). RT-related RNase H activity has also
been targeted recently with reasonable cell-based antiviral activity using hydroxypyridonecarboxylic acid derivatives (Fig. 18.5(9)) (Kankanala et al. 2016). Compounds
containing the Imidazole-amide biaryl scaffold (Fig. 18.5(10)) have also shown
good overall RT activity, which promises a new class of alternative compounds
(Chong et al. 2012). Molecular simulation-based design of pyrimidine sulfonylacetanalides (Fig. 18.5(11)) has shown very good activity against clinically relevant
N. Ranjan et al.