Small-Molecule Inhibitors of HIV-1 Protease Dimerization Derived from Cross-Linked Interfacial Peptides

Shultz,; Mj, Bowman; Yw, Ham; Zhao, Xiaowen; Tora, George; Chmielewski, Jean

doi:10.1002/1521-3773(20000804)39:15<2710::aid-anie2710>3.0.co;2-p

Cited by 45 publications

(34 citation statements)

References 4 publications

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“…Additionally, inhibitors that interfere with BACE dimerization leading to an enrichment of monomers could result in a reduction of the activity of this rate-limiting enzyme for amyloid pathology, even if such BACE monomers were stable. Therapeutic disruption of dimers was already successfully shown for the human immunodeficiency virus 1 protease, which acts as a homodimer, each unit contributing one catalytic aspartate to the active site dyad (67,68).…”

Section: Discussionmentioning

confidence: 99%

Dimerization of β-Site β-Amyloid Precursor Protein-cleaving Enzyme

Westmeyer

Willem

Lichtenthaler

et al. 2004

Journal of Biological Chemistry

104

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Cleavage of the ␤-amyloid precursor protein (APP) by the aspartyl protease ␤-site APP-cleaving enzyme (BACE) is the first step in the generation of the amyloid ␤-peptide, which is deposited in the brain of Alzheimer's disease patients. Whereas the subsequent cleavage by ␥-secretase was shown to originate from the cooperation of a multicomponent complex, it is currently unknown whether in a cellular environment BACE is enzymatically active as a monomer or in concert with other proteins. Using blue native gel electrophoresis we found that endogenous and overexpressed BACE has a molecular mass of 140 kDa instead of the expected mass of 70 kDa under denaturing conditions. This suggests that under native conditions BACE exists as a homodimer. Homodimerization was confirmed by co-immunoprecipitation of full-length BACE carrying different epitope tags. In contrast, the soluble active BACE ectodomain was exclusively present as a monomer both under native and denaturing conditions. A domain analysis revealed that the BACE ectodomain dimerized as long as it was attached to the membrane, whereas the cytoplasmic domain and the transmembrane domain were dispensable for dimerization. By adding a KKXX-endoplasmic reticulum retention signal to BACE, we demonstrate that dimerization of BACE occurs already before full maturation and pro-peptide cleavage. Furthermore, kinetic analysis of the purified native BACE dimer revealed a higher affinity and turnover rate in comparison to the monomeric soluble BACE. Dimerization of BACE might, thus, facilitate binding and cleavage of physiological substrates.

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Section: Discussionmentioning

confidence: 99%

Dimerization of β-Site β-Amyloid Precursor Protein-cleaving Enzyme

Westmeyer

Willem

Lichtenthaler

et al. 2004

Journal of Biological Chemistry

104

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“…The main dimerisation region is folded as an interdigitating N-and Cterminal four stranded β-sheet. The group of Chmielewski using rational design developed inhibitors of the PR dimerisation derived from crosslinked interfacial peptides corresponding to this conserved β-sheet region and identified the minimal structure necessary for the activity of these peptides [107]. Moreover in an attempt to improve its activity a focused library on the basis of this minimized molecule was designed (compound 6) in which certain side chains were substituted by different natural and non natural amino acid side chains, see Fig (4).…”

Section: Hiv Protease Dimerisation Inhibitorsmentioning

confidence: 99%

Discovery of Inhibitors of Protein-Protein Interactions from Combinatorial Libraries

Vicent

Pérez‐Payá²,

Orzáez³

2007

CTMC

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“…In subsequent studies the inf luence of variations in both the peptide sequences and the linker were examined. Mutations in the peptide sequences led to a new inhibitor with a slightly higher IC 50 of 680 nM, but with a significantly lower molecular weight (933 g mol -1 compared with 1586 g mol -1 ) [64]. Interestingly, in this sequence a nonnatural amino acid with an appending cyclohexyl group was used.…”

Section: Dimerization Inhibitors Of Hiv-1 Proteasementioning

confidence: 99%