HIV-1 Integrase: From Biology to Chemotherapeutics

Abstract

AIDS has claimed the lives of 25 million people worldwide, an additional 40 million people are HIV-infected and new cases are being diagnosed every year. Despite the fact that HAART has moved AIDS from the category of terminal diseases to that of treatable chronic illnesses, its long-term therapeutic success may be compromised by the development of resistance to the currently used drugs. Despite the availability of RT, PR and fusion inhibitors, the development of further drugs such as inhibitors that target the third enzyme IN is essential for the clinical management of HIV-infected patients. The absence of cellular homolgues to IN and the unique nature of the reactions catalyzed by IN, make it an ideal target for drug design. Considerable progress towards designing HIV-1 IN inhibitors has been made over the last years and several lead compounds have been identified, synthesized and clinically studied. This review focuses on the existing knowledge of the biology of HIV-1 IN with emphasis on the mechanism of integration, structure and function and the technologies for measuring IN activity. This is followed by the current trends on designing HIV-1 IN inhibitors with the aid of molecular informatics and a review on the main classes of HIV-1 IN inhibitors reported this far with special emphasis on the clinical candidates.

HIV-1 IN Inhibitors: 2010 Update and Perspectives

“…To date, several proteins have been described in the PICs including MA, Vpr, or RT 139. By screening a complete library of RT-, Rev- and Vpr-derived peptides, several peptides were isolated with IN inhibitory activity (Table 10).…”

High-throughput screening using pseudotyped lentiviral particles: A strategy for the identification of HIV-1 inhibitors in a cell-based assay

“…The mechanism of HIV replication involves a complex interplay between virus and host cells, from cell attachment to release of newly assembled virions (Sorin and Kalpana, 2006). Therefore, every single step is potentially a potential target for drug discovery (Bennasser et al 2007;Esté and Telenti, 2007;Faustino et al 2007;Liu et al 2007;Salzwedel et al 2007;Zeinalipour-Loizidou et al 2007).…”

Human Immunodeficiency Viruses Types 1 and 2

“…The viral reverse transcriptase synthesizes a cDNA copy of the virus that is transported to the nucleus; viral integrase is then involved in proviral integration. Integration of HIV-1 appears to be random but may be infl uenced by host factors [ 179 ]. Once integrated into the host chromosome, the virus is replicated like a cellular gene and incorporated into the progeny cells.…”