New HIV inhibitors
More than 40 million people have died of AIDS-related causes since the beginning of the HIV epidemic and over 35 million are still infected with the virus. Anti-retroviral therapies that target key processes of the viral replication cycle are potent but they fail to eradicate the virus. Furthermore, several clinical failures have been recorded due to the emergence of drug resistance due to the high mutational capacity of HIV. There is an imminent need for alternative strategies to tackle HIV. To overcome antiretroviral drug-resistance, the THINPAD (Targeting the HIV-1 nucleocapsid protein to fight antiretroviral drug resistance) project proposed to develop novel anti-HIV agents targeting the HIV nucleocapsid protein (NC). The consortium worked under the rationale that fighting antiretroviral drug resistance requires protein targets that are highly conserved among phylogenetically distant viral strains and do not evolve in response to pressure by currently used drugs. NC constitutes one of the most conserved sequences of HIV and is required for viral replication, rendering it an ideal therapeutic target. Of particular interest is the fact that several point mutants of NC lead to fully non-infectious defective viruses since NC works with reverse transcriptase and integrase in reverse transcription and integration steps. The team designed and developed novel NC inhibitors (NCIs), which are active against commonly occurring HIV drug-resistant strains. Following optimisation of the pharmacokinetics and ADMETox (Absorption, distribution, metabolism, excretion and toxicity) profiles of these compounds, mechanistic studies were performed. Some NCIs worked by interfering with viral replication and also inhibited the Gag-mediated steps during the late phase of the HIV lifecycle. Interestingly, all of the tested NCIs exhibited moderate inhibition of the HIV integrase. One NCI in particular, additionally targeted the reverse transcriptase and the HIV NC. Overall, the activities of the THINPAD partners led to one patent application, clearly demonstrating that the consortium was able to translate research results into industry. Inhibition of the highly conserved HIV NC protein could be used alone or in combination with other drugs to ensure full eradication of the virus.
Keywords
HIV, drug resistance, THINPAD, nucleocapsid protein, integrase