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Title: Disubstituted BIS-THF moieties as new P2 ligands in nonpeptidal HIV-1 protease inhibitors
Author: Hohlfeld, Konrad
ISNI:       0000 0004 2727 0545
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2011
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HIV-1 protease inhibitors (PIs) remain a powerful tool in the battle against HIV. The recently approved nonpeptidal HIV-protease inhibitor darunavir has been reported to be highly active against the wild-type virus as well as against a series of mutant strains. A rigid bis-tetrahydrofuran (bis-THF) moiety, with its two well-positioned hydrogen bond acceptors, has proven to play a crucial role in the interaction of darunavir with the enzyme. Based on the darunavir structure, a series of novel disubstituted bis-THF containing HIV-1 protease inhibitors have been developed, which show very good activities against wild-type HIV-1 protease as well as a panel of multi-PI resistant mutant strains. In particular, PIs have been synthesised that show equivalent and greater activity for mutant strains compared to wild-type HIV-1 protease. The new ligands are derived from a selectively protected bis-THF diol scaffold, the synthesis of which has been developed in our group. Alongside the synthesis, a design rational, as well as results from biological testing and molecular modelling will be described.
Supervisor: Linclau, Bruno Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD Chemistry