435
affinities (Wannberg et al. 2006). Novel isosorbide-derived P2 ligands (Fig. 18.8(29))
sharing the Darunavir cores have also shown picomolar affinities, thus opening several avenues to take drug-resistance challenges (Qiu et al. 2014).
18.4.2 Other New Targets
In addition to the above discussed inhibitors, a few other processes are being targeted
to develop a new class of inhibitors. Prime of them are maturation and capsid assembly inhibitors. Maturation inhibitors, albeit inhibiting the functions of protease, are
different from protease inhibitors in that they do not directly bind to the protease
enzyme to block its catalytic activity. Rather they bind to a segment of Gag polyprotein disrupting the protease-mediated conversion of p25Gag (CA/SP1) to mature p24
protein (Liu et al. 2016). Proteolytic cleavage of Gag polyprotein releases HIV-1 capsid protein, which reassembles into a cone-shaped structure containing viral RNA and
other necessary proteins (e.g. RT, integrase, protease) (Tremblay et al. 2012). Proper
assembly of capsid is mandatory for the infectivity of the new virus. Therefore, capsid
assembly inhibitors are also being explored as a new type of anti-HIV drug. The interaction of rev response element (RRE) with the rev protein is essential for viral replication (Luedtke and Tor 2003). A line of rev- RRE interaction inhibitors have been
designed and are being explored as an alternative drug target. Immunotherapy and
gene therapy-based efforts have also been tried for HIV treatment.
18.5 Future Perspectives
Development of combination therapies such as the HIV-AIDS-related HAART have
helped us explore new cumulative and complementary approaches to a desired
action. Advancements in the computational methods have significantly curtailed
lengthy screening efforts for the lead identification and have provided alternatives
for structural understanding of a drug-receptor binding. Despite this progress, the
growing emergence of drug resistance and fast viral mutation has always reminded
us to be vigilant to meet the challenges of the future. While lead optimization has
been relatively faster in recent years, the long path of clinical trials has always been
a limiting factor. A drug making it to the market has to go through all stringent
checks for its adverse actions, which requires a longer time frame for data compilation and the willingness of several patient groups for a new drug trial. Clearly these
issues are big roadblocks in a fast drug development and continue to be a problem
whose efficient solutions are not in place yet.
However, advancements in structural biology, most notably by the development of
high-resolution crystallographic and Nuclear Magnetic Resonance (NMR) techniques, have helped us understand several biologically relevant targets with fairly
decent details of their active site. Understanding of the active site and chemically
important functional groups in the vicinity of the active binding site has greatly aided
in structure-guided drug- design efforts. Moreover, the biochemical functional
18 Novel Targets and Advancements in Drug Discovery: The Case of HIV-AIDS
affinities (Wannberg et al. 2006). Novel isosorbide-derived P2 ligands (Fig. 18.8(29))
sharing the Darunavir cores have also shown picomolar affinities, thus opening several avenues to take drug-resistance challenges (Qiu et al. 2014).
18.4.2 Other New Targets
In addition to the above discussed inhibitors, a few other processes are being targeted
to develop a new class of inhibitors. Prime of them are maturation and capsid assembly inhibitors. Maturation inhibitors, albeit inhibiting the functions of protease, are
different from protease inhibitors in that they do not directly bind to the protease
enzyme to block its catalytic activity. Rather they bind to a segment of Gag polyprotein disrupting the protease-mediated conversion of p25Gag (CA/SP1) to mature p24
protein (Liu et al. 2016). Proteolytic cleavage of Gag polyprotein releases HIV-1 capsid protein, which reassembles into a cone-shaped structure containing viral RNA and
other necessary proteins (e.g. RT, integrase, protease) (Tremblay et al. 2012). Proper
assembly of capsid is mandatory for the infectivity of the new virus. Therefore, capsid
assembly inhibitors are also being explored as a new type of anti-HIV drug. The interaction of rev response element (RRE) with the rev protein is essential for viral replication (Luedtke and Tor 2003). A line of rev- RRE interaction inhibitors have been
designed and are being explored as an alternative drug target. Immunotherapy and
gene therapy-based efforts have also been tried for HIV treatment.
18.5 Future Perspectives
Development of combination therapies such as the HIV-AIDS-related HAART have
helped us explore new cumulative and complementary approaches to a desired
action. Advancements in the computational methods have significantly curtailed
lengthy screening efforts for the lead identification and have provided alternatives
for structural understanding of a drug-receptor binding. Despite this progress, the
growing emergence of drug resistance and fast viral mutation has always reminded
us to be vigilant to meet the challenges of the future. While lead optimization has
been relatively faster in recent years, the long path of clinical trials has always been
a limiting factor. A drug making it to the market has to go through all stringent
checks for its adverse actions, which requires a longer time frame for data compilation and the willingness of several patient groups for a new drug trial. Clearly these
issues are big roadblocks in a fast drug development and continue to be a problem
whose efficient solutions are not in place yet.
However, advancements in structural biology, most notably by the development of
high-resolution crystallographic and Nuclear Magnetic Resonance (NMR) techniques, have helped us understand several biologically relevant targets with fairly
decent details of their active site. Understanding of the active site and chemically
important functional groups in the vicinity of the active binding site has greatly aided
in structure-guided drug- design efforts. Moreover, the biochemical functional
18 Novel Targets and Advancements in Drug Discovery: The Case of HIV-AIDS