gms | German Medical Science

10. Kongress für Infektionskrankheiten und Tropenmedizin (KIT 2010)

Deutsche Gesellschaft für Infektiologie,
Deutsche AIDS-Gesellschaft,
Deutsche Gesellschaft für Tropenmedizin und Internationale Gesundheit,
Paul-Ehrlich-Gesellschaft für Chemotherapie

23.06. - 26.06.2010, Köln

“Dimerization inhibitors” of HIV-1 protease: from interface targeting peptides to triterpenes

Dimerisationshemmer der HIV-1 Protease: von "interface" Peptiden zu Triterpenen

Meeting Abstract

Suche in Medline nach

  • H.J. Schramm - MPI für Biochemie, i.R., Oettingen, Germany
  • W. Schramm - Ludwig-Maximilians-Universität München, Germany

10. Kongress für Infektionskrankheiten und Tropenmedizin (KIT 2010). Köln, 23.-26.06.2010. Düsseldorf: German Medical Science GMS Publishing House; 2010. DocP14

doi: 10.3205/10kit070, urn:nbn:de:0183-10kit0705

Veröffentlicht: 2. Juni 2010

© 2010 Schramm et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen ( Er darf vervielfältigt, verbreitet und öffentlich zugänglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.



The two identical subunits of HIV protease (PR) are connected by a β-sheet of four end segments. The terminal peptides disrupt the PR dimer into inactive subunits (“dimerization inhibitors”, DIs). Highly active DIs have been derived, e.g. Palmitoyl-YE(X) [X = Tyr, thyronine, etc.], Ki ~5 nM. DIs act in synergy and should also inhibit therapy mutants. Some inhibitors abrogate viral replication completely but are still too toxic for therapy.

Methods: Computer modeling (InsightII): binding data of the triterpenes to monomeric PR have been checked by determining the binding energy difference between PR bound and free inhibitors.

New results: Modelling of new triterpene inhibitor DIs propose a rigid scaffold with 2 carboxyls ~1.04 nm apart (medicagenic, quillaja acid). 3 interactions to PR are necessary: 3OH (+2OH) to R8, 4COO to R87 (+T26), 28COO to P1, H69. Similar betulinic acid 3-OH-esters (Bevirimat) show “maturation inhibition”.

Possible new approaches.

Inhibitors of auto-processing. During maturation, PR is released from the GagPol precursor poly-protein by the auto-procession step. PR auto-cleaves the peptide strands “in cis”, the first step is removal of one N-terminal p6* part. Modelling suggests that inhibitors against the auto-processing complex can be designed, e.g. partly N-alkylated PQITW(D-Asn).
Cleavable DI oligopeptides
Some PIs consist only of natural amino acids (e.g. ISYEL-OH, Ki 0.05 µM), this allows the approach of stable transfer of genes into cells which code for oligomers of PR cleavable inhibitors, e.g. (-YEFSYDL-)n. After synthesis in the infected cells, they are cleaved (only) by PR releasing inhibitors. Peptides suitable for such “suicide” constructs were identified, they carry PR C- and N-terminal cleavage segments, e.g H-YEFSYDL-OH, Ki 0.05 µM.
For the related retroviral HTLV-1 PR a similar suicide inhibitor approach is possible. Toxic proteins X can be set free in the cells using HTLV cleavage segments, e.g. (LSIPL-X-PPMVG)n.
Natural occurring DIs. PR cleavage and PR inhibitory sequence – e.g. -TLNF- – are identical and occur in many natural proteins: p6* (HIV), HERV-K, Q8NA00, FLJ360. This suggests that endogenous proteins - after PR cleavage to set free a C-terminal segment - may be able to interfere with the dimerization of PR (or the PR active site) and modulate disease progress.
Similar dissociative activity may be possible for other β-sheet aggregates (Alzheimer) by related (or identical) compounds.