Since the discovery of HIV as the etiology for AIDS 30 years ago, major
progress has been made, including the discovery of drugs that now control the disease.
Integration of the HIV-1 DNA is required and essential to maintain the viral DNA in
the infected cell. Integration process occurs in several events, mainly in
endonucleolytic processing of the 3’ ends of the viral DNA and strand transfer or
joining of the viral and cellular DNA. The design and discovery of integrase inhibitors
were first focused on targeting the catalytic site of IN with a specific effect on strand
transfer. Several integrase inhibitors were developed clinically. Here, we reviewed the
integrase (IN) inhibitors from the discovery of the first compounds 20 years ago to the
approval of two highly effective IN strand transfer inhibitors, raltegravir and
elvitegravir, and the promising clinical activity of dolutegravir. We divide the
development of integrase inhibitors into six parts, which are diketo acids, peptides,
nucleotides, natural compounds and biological product, polyhydroxylated aromatic
compounds and other inhibitors. After summarizing the molecular mechanism of
integrase inhibitors, we discuss the remaining challenges. Those include: overcoming
resistance to clinical drugs, long-term safety, cost of therapy, and the development of
new classes of inhibitors.
Keywords: Diketo acids, HIV-1 integrase inhibitors, Natural compounds and
biological product, Nucleotides, Peptides, Polyhydroxylated aromatic compounds.
