Conformationally Constrained Peptide Analogues of pTyr-Glu-Glu-Ile as Inhibitors of the Src SH2 Domain Binding

Nam, Nguyen Hai; Ye, Guofeng; Sun, Gongqin; Parang, Keykavous

doi:10.1021/jm040008+

Cited by 54 publications

(51 citation statements)

References 35 publications

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“…The approximate 10-50-fold higher affinity for monobodies (K d as low as 118 nM) compared to SIM peptides (K d ∼ 4-6 μM; ref. 18) is similar in magnitude to affinity increases for cyclic and disulfide constrained peptides over their linear equivalents (27)(28)(29), supporting our view.…”

Section: Discussionsupporting

confidence: 85%

Isoform-specific monobody inhibitors of small ubiquitin-related modifiers engineered using structure-guided library design

Gilbreth¹,

Truong

Madu

et al. 2011

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

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Discriminating closely related molecules remains a major challenge in the engineering of binding proteins and inhibitors. Here we report the development of highly selective inhibitors of small ubiquitin-related modifier (SUMO) family proteins. SUMOylation is involved in the regulation of diverse cellular processes. Functional differences between two major SUMO isoforms in humans, SUMO1 and SUMO2∕3, are thought to arise from distinct interactions mediated by each isoform with other proteins containing SUMOinteracting motifs (SIMs). However, the roles of such isoformspecific interactions are largely uncharacterized due in part to the difficulty in generating high-affinity, isoform-specific inhibitors of SUMO/SIM interactions. We first determined the crystal structure of a "monobody," a designed binding protein based on the fibronectin type III scaffold, bound to the yeast homolog of SUMO. This structure illustrated a mechanism by which monobodies bind to the highly conserved SIM-binding site while discriminating individual SUMO isoforms. Based on this structure, we designed a SUMO-targeted library from which we obtained monobodies that bound to the SIM-binding site of human SUMO1 with K d values of approximately 100 nM but bound to SUMO2 400 times more weakly. The monobodies inhibited SUMO1/SIM interactions and, unexpectedly, also inhibited SUMO1 conjugation. These high-affinity and isoform-specific inhibitors will enhance mechanistic and cellular investigations of SUMO biology.protein engineering | molecular recognition | posttranslational modification | antibody mimic | fibronectin type III domain

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Section: Discussionsupporting

confidence: 85%

Isoform-specific monobody inhibitors of small ubiquitin-related modifiers engineered using structure-guided library design

Gilbreth¹,

Truong

Madu

et al. 2011

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

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“…The propensity of the eight octapeptides to assume secondary structures correlated with their inhibitory activities. Previous studies have shown entropy-mediated gains in affinity by constraining the conformational freedom of ligands (37)(38)(39)(40)(41)(42). In the present study, spontaneous prestructuring of the peptide might reduce the entropic penalty associated with formation of a peptide/hTS complex.…”

Section: Resultsmentioning

confidence: 57%

Protein–protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase

Cardinale

Guaitoli

Tondi

et al. 2011

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

157

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The undersigned authors note the following: "We wish to bring to your attention an issue regarding our PNAS publication referenced above. Although we cite our earlier PNAS publication (see ref. Figs. 2 and 3 display the UWHBs for Hb β-subunit (pdb.1bz0, chain B) and human cellular prion protein (pdb.1qm0) (12)(13)(14). Within the natural interactive context of the Hb subunit, the UWHBs signal crucial binding regions (24): UWHBs (90, 94), (90, 95) are associated with the β-FG corner involved in the quaternary α1β2 interface; UWHB (5, 9) is adjacent to Glu-6 which in sickle cell anemia mutates to Val-6 and is located at the Val-6-(Phe-85, Leu-88) interface in the deoxyHbS fiber."The following text in the section titled 'Toward a Structural Diagnosis' on page 6449 of our text is similar to the text beginning in the last paragraph on page 2392 in ref. 23:The distribution of proteins according to their average extent of hydrogen bond wrapping and their spatial concentration of structural defects is shown in Fig. 5 (see also ref. 23). The sample of 2,811 PDB proteins is large enough to define a reliable abundance distribution with an inflection point at ρ = 6.20. The integration of the distribution over a ρ-interval gives the fraction of proteins whose ρ lies within that range. Of the 2,811 proteins examined, 2,572 have ρ > 6.20, and none of them is known to yield amyloid aggregation under physiological conditions entailing partial retention of structure. Strikingly, relatively few disease-related amyloidogenic proteins are known in the sparsely populated, underwrapped 3.5 < ρ < 6.20 range, with the cellular prion proteins located at the extreme of the spectrum (3.53 < ρ < 3.72)....The range of H-bond wrapping 3.5 < ρ < 4.6 of 20 sampled PDB membrane proteins has been included in Fig. 5 for comparison. As expected, such proteins do not have the stringent H-bond packing requirements of soluble proteins for their H bonds at the lipid interface. Thus, this comparison becomes suggestive in terms of elucidating the driving factor for aggregation in soluble proteins: Although the UWHB constitutes a structural defect in a soluble protein because of its vulnerability to water attack, it is not a structural defect in a membrane protein. The exposure of the polar amide and carbonyl of the unbound state to a nonpolar phase is thermodynamically unfavorable (22). The virtually identical ρ value for human prion and outer-membrane protein A (Fig. 5) is revealing in this regard.Furthermore, all known amyloidogenic proteins that occur naturally in complexed form have sufficient H-bond wrapping within their respective complexes (ρ value near 6.2). Their amyloidogenic propensity appears only under conditions in which the protein is dissociated from the complex (compare Fig. 5). This finding is corroborated by the following computation. If an intramolecular hydrogen bond is underwrapped within the isolated protein molecule but located at an interface upon complexation, then to determine its extent of wrapping within the complex, we take ...

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“…The DKP scaffold is widely found in compounds of biological interest and could serve as a drug template with appropriate arrayed pharmacophores. To this point, studies showed that the replacement of a DKP cis-amide bound with structurally similar (z)-alkene units could provide DKP mimetics (16) as novel templates for creating drug-like structures [50][51][52][53][54]. Therefore, adequate linear dipeptide derivatives could act as prodrugs for DKP-based drugs.…”

Section: Peptide Carriers A) Peptide Cyclization and Prodrug Designmentioning

confidence: 99%

Cyclization-activated Prodrugs

2007

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Many drugs suffer from an extensive first-pass metabolism leading to drug inactivation and/or production of toxic metabolites, which makes them attractive targets for prodrug design. The classical prodrug approach, which involves enzyme-sensitive covalent linkage between the parent drug and a carrier moiety, is a well established strategy to overcome bioavailability/toxicity issues. However, the development of prodrugs that can regenerate the parent drug through non-enzymatic pathways has emerged as an alternative approach in which prodrug activation is not influenced by inter-and intraindividual variability that affects enzymatic activity. Cyclization-activated prodrugs have been capturing the attention of medicinal chemists since the middle-1980s, and reached maturity in prodrug design in the late 1990s. Many different strategies have been exploited in recent years concerning the development of intramoleculary-activated prodrugs spanning from analgesics to anti-HIV therapeutic agents. Intramolecular pathways have also a key role in two-step prodrug activation, where an initial enzymatic cleavage step is followed by a cyclization-elimination reaction that releases the active drug. This work is a brief overview of research on cyclization-activated prodrugs from the last two decades.

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Conformationally Constrained Peptide Analogues of pTyr-Glu-Glu-Ile as Inhibitors of the Src SH2 Domain Binding

Cited by 54 publications

References 35 publications

Isoform-specific monobody inhibitors of small ubiquitin-related modifiers engineered using structure-guided library design

Isoform-specific monobody inhibitors of small ubiquitin-related modifiers engineered using structure-guided library design

Protein–protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase

Cyclization-activated Prodrugs

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