Identification of cellular factors important for HIV-1 replication by forward chemical genetics.
Doctoral thesis, UCL (University College London).
The AIDS epidemic is a major global health problem with an estimated 33.2 million infected with HIV, mainly in Sub-Saharan Africa. Effective drugs have been developed that are targeted against selected viral proteins but HIV mutates very rapidly and invariably becomes resistant to available drugs, even when they are used in combination. A complementary, yet little explored possibility is to develop new drugs that target and block cellular factors necessary for virus replication. Host factors mutate less rapidly and hence HIV-1 drug resistance may be less likely to emerge. During my Ph.D. project I have performed a small chemical screen of inhibitors of ATP-dependent DNA motors to test their ability to inhibit HIV infection. The approach called “chemical genetics” consists in screening a library of small compounds for their ability to inhibit HIV infection, the identification of the step of the viral cycle inhibited, the identification and validation of the target and the improvement of the compound potency by chemical modification and, where possible, rational drug design. The screen revealed that Coumermycin A1 (C-AI), a gyrase B inhibitor coumarin antibiotic, potently suppressed HIV-1 infection. CA1 impaired HIV-l integration and early gene expression in a Tat-independent way by targeting two host factors. A search for conserved ATPase domains capable of binding coumarin antibiotics revealed several potential targets, including DNA Topoisomerase II and Hsp9O. Topoisomerase II played no significant role in HIV-1 infection, however Hsp9O was required for early gene expression. Docking studies revealed two C-A1 binding pockets in the C-terminus of Hsp9O. The sensitivity to C-Al-mediated inhibition of viral gene expression mapped to p24 CA protein, suggesting that CA may affect Hsp90 function to prime cells for infection. Coumermycin Al, developed by Roche in the early 1970s shows a good pharmacological profile but is not efficiently adsorbed by the gastrointestinal tract needing therefore structural improvement to be considered as anti-HIV drug. Hsp90 inhibitors might be used as antiretrovirals in selected AIDS patients.
|Title:||Identification of cellular factors important for HIV-1 replication by forward chemical genetics|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Infection and Immunity (Division of) > Research Department of Infection|
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