HIV protease plays a crucial role in the viral life cycle by processing the
viral Gag and Gag-Pol polyproteins into structural and functional proteins essential for
viral maturation. Inhibition of HIV-1 protease leads to the production of noninfectious
virus particles and hence is an important therapeutic target for antiviral therapy in
AIDS patients. It is a 99-residue protein belonging to the class of aspartic acid
proteases, functioning as a catalytic dimer. The inclusion of protease inhibitors (PIs) in
highly active antiretroviral therapy has significantly improved clinical outcomes in
HIV-1 infected patients. The first HIV-1 protease inhibitors were developed in the mid-
1990s and approved for clinical practice by 1995. So far ten such drugs have been
approved for HIV treatment by the US Food and Drug Administration, including
saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, fosamprenavir,
atazanavir, tipranavir and darunavir, and broadly divided into first, second, and third
generations. Expect for tipranavir, all of them are competitive peptidomimetic HIV
protease inhibitors, which are able to mimic the transition state of HIV-1 protease
substrates. However, the rapid emergence of drug-resistant HIV-1 strains and the
appearance of cross-resistance are severely limiting the long-term treatment options, all
of these make it urgent to develop new HIV protease inhibitors to combat the global
disease. Thus, numerous efforts have been made in the design and synthesis of novel
protease inhibitors with broad-spectrum activity against multidrug-resistant HIV-1
variants by medicinal chemists. Recently, considerable attention has been paid to the
development of newer compounds capable of inhibiting wild-type and resistant HIV-1
protease. In this review, we have made an attempt to provide an overview on newly developing peptidomimetic and non-peptidomimetic PIs, and treatment of related
recent patents in the development of novel PIs.
Keywords: Antiviral efficacy, Development, HIV, Modify, Peptidomimetic PIs,
Non-peptidomimetic PIs, Toxicities, Treatment.
