Schramm, H.J.;König, S.;Büttner, J.;Schramm, W. - Interface targetring inhibitors of HIV-1 Protease

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Title: Interface targetring inhibitors of HIV-1 Protease	P149
Schramm, H.J.; König, S.; Büttner, J.; Schramm, W. schramm.hj@t-online.de LMU München

3-Mer lipopeptides, derived from the interface segments of HIV protease (PR) inhibit PR and act as potent interface targeting "dimerization inhibitors" 1),2). They should also inhibit therapy mutants since the interface is very conserved and the (mutated) active site not involved. In order to improve inhibition and metabolic stability, "modified peptides" were investigated 3).

Modified Peptide Related Peptide IC50 (µM)
___________________________________________________________________________
Ac-Ser-Tyr-Glu-Leu 55
Ester of Ac-Ser-Tyr-Glu-Leu (R = 2-0CH2-pyridyl) 13(Ki-dim = 0.3)
t-Buac-Phe-Asn-Tyr-Glu-Trp 70
Ester of Phe-Asn-Tyr-Glu-Trp (R = 2-0CH2-pyridyl) 33
Cyclic all-D-peptide c(-gly-ser-tyr-glu-tyr-NH-), 320
Peptoid (H-Nabu-Ntyr-Nasp-Ntrp-OH) 21
Pam-Tyr-Glu-Thyronine 1) 0.005 (Ki-dim)
Pam-Tyr-Glu-Leu 1) 0.01 (Ki-dim)
Octyl-Tyr-Glu-Leu-OH no inhibition
Dodecyl-Tyr-Glu-Leu-OH ("mixed inhibition") 0.2
Pam-Ser-Tyr-Glu-Thyronine ("mixed inhibition") ca. 0.05
H-Tyr-Glu-Thyronine 10
Phenylbutyroyl-Tyr-Glu-Leu ("mixed inhibition") 10
H-(D-homo-Phe)-Tyr-Glu-Leu-OH ("mixed inhibition") 5

Esterification maintains the activity while neither peptoids nor retro-inverso peptides show improvement since backbone modification disturbs hydrogen bonding 3). Modifications of the N-terminal blocking group shows that a minimum length of 12 C atoms is needed in order to obtain interface binding. For the construction of ß-sheet targeting inhibitors, computer modelling suggests the corresponding D-amino acids and substituted aminoglycins as replacements. The results may be helpful for defining rules for the design of inhibitors, applicable to many composite enzymes (or protein complexes). The steps: a) identification of (weakly but specifically) binding peptides (e.g. pro-peptides), b) attachment of lipids (or other groups) for unspecific binding re-enforcement, c) transformation into "modified peptides" or peptidomimetics with improved ADEME values. The question of specificity of ß-sheet inhibitors arises: Some PR interface inhibitors also inhibit other ß-sheet enzymes, e.g. ß-secretase, and interfere with amyloid formation (Aß-aggregation). On the other hand, some serpin insertion peptides with ß-sheet propensity also inhibit PR.

[1] Schramm, H.J. et al., Biol. Chem., 380, 593 (1999).
[2] Dumond, J., Bogetto, N., Reboud-Ravaux, M., Schramm, H.J., W. Schramm, in preparation.
[3] König, S., et al. Proc. 7th Int. Symp. Solid Phase Synth., Southampton (2001), in press.