final program.qxd - Parallels Plesk Panel

PP 2.17
Interface targeting peptides as inhibitors of HIV-1 protease
Schramm, Hans J., Schramm, Wolfgang
Dept. Haemostaseology, LMU, Ziemssenstr. 1, 80336 München, Germany
While most inhibitors (PIs) of HIV protease (PR) target the active site, some peptides
derived from the terminal segments act by dissociating the PR dimer - a ß-sheet
interface structure - into inactive subunits ("dimerization inhibitors"). The modes of action
can be distinguished by kinetic analysis from other inhibition modes. From these peptides,
highly active PIs were developed [1-3]. The best inhibitors are lipid-blocked tripeptides
with C-terminal thyronine (T0) or thyroxine (T4), e.g. Palmitoyl-Tyr-Glu-(Tx)-OH with Ki ~5
nM [2]. Tyr and (Tx) are anchor residues. They seem to be the most potent specific
reagents for protein/protein dissociation and also of interest for 'interactome' projects.
Since large side chains as in thyronine do not fit into the active site sub-sites of dimeric
PR, the dissociative mechanism is proved. The cell pH of 7.4 also lowers dimer stability.
Interface targeting PIs should also inhibit therapy mutants since the interface is well
conserved and mutants (e.g. V82T) have lower dimer stability. Some of the inhibitors
(Pam-YET0) abrogate viral replication, but only few have been tested so far. Tests using
PI-resistent virus strains are under way. There is a good chance to convert the peptides
into cheap "modified peptides" and mimetics (peptoids, ester prodrugs, retro-inverso,
cyclic and D-form peptides [3]). Some triterpene and steroid derivatives with low toxicity
(ursolic, oleanolic acids, ursodesoxycholic acid) also inhibit PR in this way [4] and may be
useful in cocktails.
Some PIs interact also with other beta-sheet proteins like beta-secretase or amyloid
aggregates (Alzheimer Aß). Vice versa, PR is inhibited by beta-sheet insertion peptides
from serpin enzymes (Ac-AMFLEAIP-Nle-E from a1-Antitrypsin (IC50 25 µM) containing
the inhibitory TLNF sequence) [5]. This suggests that endogenous proteins may be able
to interfere with the dimerization of PR or other HIV proteins, in this way modulating
disease progress. Similar PR cleavage and inhibitor sequences occur in virus and cell
proteins, e.g. p6*, endogenous retroviruses, proteins Q8NA00, FLJ360 (VSYSF), etc..
1) Schramm, H.J. et al.. Biol. Chem. (99) 380, 593. 2) Dumond, J., et al.. Biochem. Pharm.
(03) 65, 1097. 3) König, S., et al. (03), in: R. Epton (Ed.). Mayflower W.W., Proc. 6 th Int.
Symp. Solid Phase Synth. 24, 107. 4) Quéré, L. et al. (96), B.B.R.C. 327, 484. 5)
Schramm. H.J (04). J. Peptide Sci., Supplement H74.
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