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- Hultén, Johan
(author)
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Cyclic sulfamides as HIV-1 protease inhibitors : Synthesis, X-ray structure analysis and structure-activity relationship
- 1999
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Doctoral thesis (other academic/artistic)abstract
- Human Immunodeficiency Virus (HIV) is the causative agent of Acquired Immune Deficiency Syndrome (AIDS). Inhibition of HIV-1 protease leads to immature and non-infectious viral particles. The synthesis of a number of cyclic HIV-1 protease inhibitors and the subsequent evaluation in an enzyme assay is presented in this thesis. A centrally positioned water molecule (W301), unique to retroviral proteases, guided the design ofthe inhibitors.A synthetic procedure utilising carbohydrates as chiral starting materials has been used to gain control of the stereochemistry of the target compounds. Synthesis of four C2-symmetric cyclic urea inhibitors revealed the importance of correct stereochemistry in rigid cyclic structures for activity. According to the X-ray crystal structures of the cyclic inhibitors, in complex with the protease, a displacement of the water molecule W301 by aurea carbonyl, or alternatively by a sulfamide group was accomplished. Changing the water-mimicking group from urea to sulfamide resulted in an unexpected non-symmetric binding mode as deduced from comparison of the X-ray crystal structure of a urea and a sulfamide inhibitor in complex with the protease. A small X-ray structure of a sulfamide inhibitor in absence of the protease established that thenon-symmetric conformation of the inhibitor was an inherent feature of the sulfamide scaffold and not induced by the protease.In an attempt to establish the structure activity relationship (SAR) of the sulfamide class of inhibitors, symmetric and non-symmetrically substituted sulfamide inhibitors were prepared. A comparative molecular field analysis (CoMFA) was performed to rationalise the SAR and give a model of predictive value. The cyclic inhibitors wereevaluated against a series of mutant forms of the protease and found to have a considerably lower affinity towards I84V and V82A than towards the wild type enzyme.
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