Chemistry Reference
In-Depth Information
favors the emergence of resistant mutants when selection pressure is exerted by
antiretroviral agents. Passaging HIV-1(BAL) serially under pressure by RC-101
caused relatively minor changes in viral susceptibility. Emergent viral isolates had
three amino acid changes in their envelope glycoprotein, one was in a CD4-
binding region of gp120, and two in heptad repeat domains of gp41. Each mutation
replaced a neutral or electronegative residue with one that was positively charged.
Single-site mutations in heptad repeat-2 replacing anionic residues with cationic
ones, often generated viruses with impaired infectivity [9] .
26.10
It Takes Two to Tangle
Can one very small molecule use different mechanisms to prevent HIV-1 and IAV?
Our answer will begin with an easily overlooked technical detail. The studies with
IAV [6] were performed under serum-free conditions and the HIV- 1 studies were
done in medium containing fetal bovine serum. These conditions were chosen
because IAV infects host cells on serum-free surfaces in the upper or lower airways
and because the HIV-1 targets required serum-containing media for optimal
growth and survival (for infl uenza hemagglutinins and therapy by sialidase inhibi-
tors, please see Chapters 17.3.1 and 28.2 ).
Fetuin is a heavily glycosylated protein that is one of the most abundant proteins
in fetal bovine serum. It harbors three sites for
N
- glycosylation (complex - type, bi -
and triantennary
N
- glycans) and also
O
-glycosylation (core 1) (for details, please
see Chapters 6 and 7). Fetuin binds to RCs with high affi nity and competes for its
binding to cell-surface glycoproteins [5]. Under the serum-free conditions, RCs
formed a tangled barrier of surface glycoproteins whose presence barred the entry
of IAV virus [6] . RC - mediated hemagglutination (Figures 26.4 and 26.5 ) probably
resulted from entangled surface glycoproteins and was also inhibited by serum.
The reversible cross-linking of surface glycoproteins by
- defensins is a form
of polymerization in which the monomers (glycoproteins) cross- linked
θ
by
θ
-defensins from the cell surface or other-
wise acting as lattice breakers, free- fl oating glycoproteins can prevent barrier for-
mation. Thus, in a serum-containing environment, a mechanism based on
electrostatic binding to heptad repeat-2 of gp41 will predominate, whereas a barrier
mechanism can exist in other environments.
-defensins form a lattice. By diverting
θ
26.11
Which Human
α
- and
θ
- Defensins Are Lectins?
The author has investigated
-defensins for three decades, and lived with them
personally for seven, so he will not feign indifference to these peptides. Perhaps
because
α
α
-defensins are expressed in humans
and
mice, whereas
θ
- defensins are
expressed only by non-human primates,
α
- defensins have received considerably
