This project elucidates the fundamental molecular design of heparins and heparan sulfates (H/HS) and studies the structural basis of their specific modulations of protein and cell membrane in diverse normal and diseased physiological systems, using various biological, biochemical, and physical approaches. We examined H/HS as a modulator of viral infectivity, studied structure-function relations of a heparin-mimetic drug composed of a mixture of sulfated oligoxylans (S-oligoS) which, as does heparin, inhibits infectivity of HIV-1 in vitro: 1) We had shown that the capacity to inhibit HIV-1 cytotoxicity and syncytium-forming infectivity was governed by a structural specificity, and that inhibition of the two direct cell-killing mechanisms may have different structural requirements. A minimal-sized, potent antiviral component, CpF, was separable from S-oligoS having anticoagulation activity against thrombin and there was structural specificity in anticoagulation reactions. S-oligoS contained multiple D-G1cA moieties, suggesting a novel structural element, three beta 1, 4-linked xyloses with an beta 1,2-linked D-G1cA branch; 2) CpF-PkII isolated from CpF and further-purified CpF-PkII show that one or more sugars may be in the alternate chair form (axial as well as expected equatorial sulfates are found); 3) CpF inhibits the adherence of human CD4 cells to gp120-coated plastic, while S-oligoS that are inactive against HIV-1 in the above assays do not. CpF-PkI appears stable in size and charge during substitution and conjugation reactions. We are now able to develop a florescent CpF-PkI probe as a ligand for human CD4 cells to crosslink a putative S-oligoS """"""""receptor"""""""" upon photoactivation; and 4) OligoS (8-, 12-, and 14-mers) of heparin purified by function (antithrombin activation) indicate that three turns about the axis is one requirement for capacity to form helical order, greater than or equal to 12- mer, as reelected by the geometry of bound cationic ligands.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Intramural Research (Z01)
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