Design And Synthesis Novel Human Immunodeficiency Virus Associated Entry Inhibitors And Glycopeptides

HIV-1is one of the most notorious retrovirus in the world. More than33.3millionpeople are living with HIV-1. Vaccine investigation has not generated a potent drugwhich can neutralize the virus. Entry inhibitor plays an important role in anti-HIVdrugs.Carbohydrate plays an important role during the process of HIV entry. In thisthesis, we investigated the carbohydrates expressed on HIV Env protein gp120. Wesynthesized tri-mannose with the structure based on hyper-mannose type of gp120. Theglycoconjugate had been synthesized with sugar and cyclo-peptide conjugate. Theinteraction between glycopeptides and protein was detected by SPR. The interactionbetween sugar and protein is important for HIV infection.We also designed the peptide inhibitors for HIV fusion process.“Recognize–covalent bind” strategy and “recognize–cleave” strategy were designed.“Recognize–covalent bind” strategy is C34which carries an isothiocyanate group at the side chain ofAsp632through which the inhibitor can bind to target covalently. And “recognize–cleave” strategy is that C34was modified with cyclen and metel ion so that it can cleavethe target protein into small pieces. These two design for multi-functional peptideinhibitor.Moreover, a highly anti-HIV peptide inhibitor derived from C34was designed. Anartificial salt bridge was added in the6-helical bundle by substitution of lysine for Ile646.With a cholesterol modification at C-terminal, the inhibitor containing I646K mutationrepresented higher anti-viral activity than C34-cholesterol combination withoutmutation.Fmoc protected peptide synthesis is an important strategy for peptide inhibitorsdesign. Chemical ligation is the most wide used method for long peptide synthesis. Wedesigned a new type of ligation auxiliary with high yield synthesis. In addition, the wayto synthesize the peptide thioester had been optimized.