Disease relevance of Pseudopeptides

• Pseudopeptides 9-12 were found to be competitive inhibitors of wild-type HIV-1 protease in biological assays having Kis of 0.31-0.35 nM for 9, 0.16-0.21 nM for 10, 0.47 nM for 11, and 0.17 nM for 12; these inhibitors were thus approximately equipotent to the known inhibitor 14(IC50 = 0.22 nM) from which they were derived [1].
• To identify more selective inhibitors of MMP-11, a matrixin overexpressed in breast cancer, a series of phosphinic pseudopeptides bearing a variety of P(1)'-side chains has been synthesized, by parallel diversification of a phosphinic template [2].
• Similar positively charged control pseudopeptides have no effect on HIV infection even at high concentrations [3].
• Here, we show that pairs of virtual backbone torsions can also define these nine conformational forms, and that comparing these virtual torsions in dipeptides with those of backbone-modified pseudopeptides offers an improved procedure for evaluating peptidomimetics for therapeutic applications [4].

High impact information on Pseudopeptides

• For one of these pseudopeptides, we prepared fluorescent tetramers of MHC molecules and compared the staining of two T cell hybridomas [5].
• One of these pseudopeptides, containing a reduced peptide bond between residues 6 and 7 (Psi(6-7)), displayed very similar properties of binding to major histocompatibility complex (MHC) and recognition by T cell receptor transgenic T cells specific for GP33 when compared with the parent peptide [6].
• To directly investigate the role of the peptide backbone in T cell recognition, we performed a methylene-amino scan on the backbone of an antigenic peptide and measured the capacity of such pseudopeptides to bind their cognate MHC molecule, to sensitize target cells for T cell lysis, and to stimulate IL-2 secretion by two T cell hybridomas [5].
• Efficient binding of reduced peptide bond pseudopeptides to major histocompatibility complex class I molecule [7].
• The structural properties of these beta-lactam pseudopeptides have been studied by X-ray crystallography, Molecular Dynamics simulation, and NOESY-restrained NMR simulated annealing techniques, showing a strong tendency to form stable type II or type II' beta-turns either in the solid state or in highly coordinating DMSO solutions [8].

Chemical compound and disease context of Pseudopeptides

• Two pseudopeptides known to be very potent in the enzyme test (SDZ PRI 053 and CIBA 61755) also inhibit HIV-1 protease strongly in this cell growth test [9].
• In general, N-hydroxy Gly containing pseudopeptides displayed modest HIV Pr inhibition (IC50 > or = 930 nM) [10].

Biological context of Pseudopeptides

• All pseudopeptides showed affinity for the gastrin receptor, in vitro, with potencies varying from IC50 = 10(-7) to IC50 = 10(-4) M [11].
• Inhibitors of Ras protein farnesyltransferase are described which are reduced pseudopeptides related to the C-terminal tetrapeptide of the Ras protein that signals farnesylation [12].
• Partially modified retro-inverso pseudopeptides as non-natural ligands for the human class I histocompatibility molecule HLA-A2 [13].
• A structure-activity relationship study on pseudopeptides indicated that the decrease in alpha-helicity and the increase in net positive charge in the backbone, caused by the incorporation of a reduced amide bond into the peptide, both contributed to an improvement in the selectivity between lipid membranes with various surface charges [14].
• The synthetic pathway devised for the preparation of both epimers of 1 at C(5) involves a reductive amination of cyanomethyleneamino pseudopeptides with amino acid derivatives, followed by regiospecific lactamization of the resulting C-backbone branched pseudopeptides [15].

Anatomical context of Pseudopeptides

• The approach of using pseudopeptides containing changes involving the backbone, and not the orientation of side chains, may thus be promising to design potent immunogens for class II-restricted T cells [16].
• These pseudopeptides, in which the presence of unnatural and hydrophobic residues is expected to improve their penetration of the central nervous system, were shown to be very resistant to brain peptidases [17].
• The pseudopeptides selected for agonist studies were shown to act as AT(2) receptor agonists being able to induce outgrowth of neurite cells, stimulate p42/p44(mapk), and suppress proliferation of PC12 cells [18].
• Injection of Dip-allatostatin or Dip-allatostatin pseudopeptides into mated female Diploptera punctata inhibits endogenous rates of JH biosynthesis and basal oocyte growth [19].
• Anti-HIV recombinant protease assays and HIV infected cell culture assays (observation of syncytia) demonstrated the potent anti-HIV activity of this new class of pseudopeptides [20].

Associations of Pseudopeptides with other chemical compounds

• Evaluation of the resolution of the diastereomers as a function of pH of the BGE revealed that most suitable pH region for separation of the diastereomers is around the pK(a) values of the central phosphinic acid group of the pseudopeptides [21].
• Angiotensin II pseudopeptides containing 1,3,5-trisubstituted benzene scaffolds with high AT2 receptor affinity [22].
• In addition, the pseudopeptides were from 3.5-fold (MEN 10,677) to 16-fold (MEN 10548) more potent antagonists against septide than against [Sar9]SP sulfone, two agonists reportedly selective for two distinct sites/subtypes of the NK1 receptor [23].
• Application of similar strategies to NMB by formation of [DPhe8]NMB, [psi 9-10]NMB pseudopeptides, des-Met10 NMB amides, alkylamide or esters did not result in any potent NMB receptor antagonists [24].
• [DPhe12]Bn analogs; des Met14 amides, esters and alkylamides; psi 13-14 Bn pseudopeptides; and D-amino acid-substituted analogs of substance P (SP) or SP(4-11) were all synthesized and each functioned as a GRP receptor antagonist [24].

Gene context of Pseudopeptides

• The phosphinic pseudopeptides, which served as immobilized ligands for the isolation of rat BHMT, were then tested for their ability to inhibit human recombinant BHMT in solution [25].
• Four pseudopeptides were AT2 selective, while one (5) also exhibited good affinity for the AT1 receptor (K(i) = 30.3 nM) [22].
• The tachykinin (NK2) receptor-mediating contraction of the human isolated bladder to NKA was investigated by studying the affinities of eight structurally different receptor-selective antagonists (linear peptides, cyclic peptides and pseudopeptides, nonpeptide NK2 receptor antagonists) [26].
• Toward further evaluating the utility of these dipeptide mimics in the design of novel CA(1)A(2)X-based inhibitors of Ras farnesyltransferase (FTase), the conformationally constrained, diastereomeric pseudopeptides CAbuPsi[COcpCO]FM 7-9, the flexible analogue CAbuPsi[CHOHCH(2)]FM (10), and the tetrapeptide CAbuFM (6) were prepared [27].
• The cyclic pseudopeptides MEN 10,548, MEN 10,581, MEN 10,619, MEN 10,677, MEN 10,777 and MEN 10,867 were studied at tachykinin neurokinin (NK)1, NK2 and NK3 receptors on several in vitro bioassays [23].

Analytical, diagnostic and therapeutic context of Pseudopeptides

• The amount of desired linear pseudopeptides in the mixtures ranged from 67 to 90% as determined by integration of HPLC peak areas [28].
• The pseudopeptides recognized by the antisera in the indirect ELISA were not the same, however, as those recognized in the competitive ELISA [29].
• The resulting pseudopeptides divulged widely differing retentive behaviors on reversed phase high performance liquid chromatography (HPLC) [30].

References