The inhibition of human immunodeficiency virus proteases by ‘interface peptides’

Schramm, Hans J.; Boetzel, Joachim; Büttner, J.; Fritsche, Erich; Göhring, Walter; Jaeger, Ernst; König, Stephan; THUMFART, O; T, Wenger; Nagel, Norbert

doi:10.1016/0166-3542(96)00940-0

Cited by 78 publications

(81 citation statements)

References 34 publications

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“…Toward this goal, both enzyme complexes were probed with known linear peptidic inhibitors. These peptides are a C-terminal-derived hexapeptide (TVSYEL) for HIV protease that inhibits the essential ␤-sheet interactions (24), and a heptapeptide (FTLDADF) for RR that competes with binding between subunits mR1 and mR2 (25). Gratifyingly, when coexpressed with target fusions, the inhibitor peptides and not scrambled controls relieved repression of the lacZ reporter (Fig.…”

Section: Resultsmentioning

confidence: 99%

A systematic method for identifying small-molecule modulators of protein–protein interactions

Horswill

Savinov

Benkovic

2004

Proc. Natl. Acad. Sci. U.S.A.

107

159

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Discovering small-molecule modulators of protein-protein interactions is a challenging task because of both the generally noncontiguous, large protein surfaces that form these interfaces and the shortage of high-throughput approaches capable of identifying such rare inhibitors. We describe here a robust and flexible methodology that couples disruption of protein-protein complexes to host cell survival. The feasibility of this approach was demonstrated through monitoring a small-molecule-mediated protein-protein association (FKBP12-rapamycin-FRAP) and two cases of dissociation (homodimeric HIV-1 protease and heterodimeric ribonucleotide reductase). For ribonucleotide reductase, we identified cyclic peptide inhibitors from genetically encoded libraries that dissociated the enzyme subunits. A solid-phase synthetic strategy and peptide ELISAs were developed to characterize these inhibitors, resulting in the discovery of cyclic peptides that operate in an unprecedented manner, thus highlighting the strengths of a functional approach. The ability of this method to process large libraries, coupled with the benefits of a genetic selection, allowed us to identify rare, uniquely active small-molecule modulators of protein-protein interactions at a frequency of less than one in 10 million.M any regulatory processes in living organisms are often a consequence of specific protein-protein contacts, and interference with such interactions provides a means to exert control over cellular events. The de novo discovery of small molecules capable of disrupting such protein-protein complexes has been fraught with challenges, yielding very few inhibitors at a low success rate (1-3). These difficulties suggest that large, functionally diverse libraries might be essential for finding unique molecules that are capable of perturbing the intracellular levels of specific protein-protein interactions. The major challenge in sifting through such vast compound pools is the shortage of functional high-throughput assays for detection of the protein complex dissociation (4).Genetic selection is uniquely capable of identifying individual molecules with desired properties from large libraries by using whole cells as reporters and correlating host growth to a desired functional property. Unlike recently popularized affinity-based selections (5), an intracellular genetic selection can directly assay for effects on enzymatic activity or the modulation of a proteinprotein complex, thus bypassing the inherent limitations of in vitro approaches. Additionally, library members must function within the context of the entire host proteome, requiring positive candidates to have an enhanced level of selectivity for their target. This feature represents an important advantage over traditional screen-based methods in drug discovery by allowing both target affinity and selectivity to be simultaneously optimized. The application of a genetic selection to the identification of small-molecule modulators may yield both potent and selective activities as well as uniq...

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Section: Resultsmentioning

confidence: 99%

A systematic method for identifying small-molecule modulators of protein–protein interactions

Horswill

Savinov

Benkovic

2004

Proc. Natl. Acad. Sci. U.S.A.

107

159

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“…This mode of inhibition may carry the added advantage of reducing the emergence of drug-resistant strains. Several reports indicate that peptides derived from the terminal regions of the protease inhibit enzymatic activity by blocking dimer formation (11,12). However, to date this has not been confirmed structurally, either by x-ray crystallography or NMR.…”

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confidence: 96%

Revisiting Monomeric HIV-1 Protease

Louis

Ishima

Nesheiwat

et al. 2003

Journal of Biological Chemistry

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“…Because protein-protein interactions play a key role in various mechanisms of cellular growth and differentiation, and viral replication, inhibition of these interactions is a promising novel approach for rational drug design against a wide number of cellular and viral targets (17,18). Synthetic peptides that disrupt protein-protein interactions have been successfully shown to act as inhibitors of HIV-1 protease (19), HIV-1 reverse transcriptase (20), herpes simplex virus ribonucleotide reductase (21), and thymidilate synthase (22). Binding of polypeptide hormones, growth factors, or cytokines to cell surface receptors activates dimerization (oligomerization) of the receptors, which leads to the signal transduction to the interior of the cell (23).…”

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confidence: 99%

Disabling Receptor Ensembles with Rationally Designed Interface Peptidomimetics

Berezov

Chen

Liu

et al. 2002

Journal of Biological Chemistry

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Members of the erbB family receptor tyrosine kinases (erbB1, erbB2, erbB3, and erbB4) are overexpressed in a variety of human cancers and represent important targets for the structure-based drug design. Homo-and heterodimerization (oligomerization) of the erbB receptors are known to be critical events for receptor signaling. To block receptor self-associations, we have designed a series of peptides derived from potential dimerization surfaces in the extracellular subdomain IV of the erbB receptors (erbB peptides). In surface plasmon resonance (BIAcore) studies, the designed peptides have been shown to selectively bind to the erbB receptor ectodomains and isolated subdomain IV of erbB2 with submicromolar affinities and to inhibit heregulin-in- erbB2 (neu, HER2) is a member of the epidermal growth factor or HER family of tyrosine kinase receptors that also includes erbB1 (EGFR, 1 HER1), erbB3 (HER3), and erbB4 (HER4) (1-4). Overexpression of erbB receptors has been found in many types of human cancer raising the possibility that receptor-directed therapies may be useful as cancer management strategies. Greater expression of erbB2 on transformed cells than on normal epithelial tissues allows selective targeting of tumor cells using various approaches (5-13). A variety of strategies have also been developed for targeting the erbB1 receptor, including monoclonal antibodies, ligand-linked immunotoxins, tyrosine kinase inhibitors, and antisense approaches.Recently, we have reported the design of an anti-erbB2 peptide mimetic, AHNP, derived from the structure of the CDR-H3 loop of the anti-erbB2 monoclonal antibody 4D5 and demonstrated its in vitro and in vivo activities in disabling erbB2 tyrosine kinases similar to the monoclonal antibody (14 -16). We have argued that another interesting approach for disabling erbB receptor activity would be targeting protein-protein interaction surfaces. Because protein-protein interactions play a key role in various mechanisms of cellular growth and differentiation, and viral replication, inhibition of these interactions is a promising novel approach for rational drug design against a wide number of cellular and viral targets (17,18). Synthetic peptides that disrupt protein-protein interactions have been successfully shown to act as inhibitors of HIV-1 protease (19), HIV-1 reverse transcriptase (20), herpes simplex virus ribonucleotide reductase (21), and thymidilate synthase (22). Binding of polypeptide hormones, growth factors, or cytokines to cell surface receptors activates dimerization (oligomerization) of the receptors, which leads to the signal transduction to the interior of the cell (23). Although most of the receptor inhibitors developed to date have been focused on the blockade of receptor-ligand or enzyme-substrate interactions, repression of receptor-receptor interactions that accompany oligomerization might also represent an important target for disabling receptor functioning. This approach has been recently used for the design of peptidic estrogen receptor inhibitors ...

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The inhibition of human immunodeficiency virus proteases by ‘interface peptides’

Cited by 78 publications

References 34 publications

A systematic method for identifying small-molecule modulators of protein–protein interactions

A systematic method for identifying small-molecule modulators of protein–protein interactions

Revisiting Monomeric HIV-1 Protease

Disabling Receptor Ensembles with Rationally Designed Interface Peptidomimetics

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