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Results for “rational design”

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PubMed1996

Rational design of receptor partial agonists and possible mechanisms of receptor partial activation: a theory.

Partial activation of membrane receptors using specific partial agonists may be particularly beneficial to the treatment of some chronic diseases like congestive heart failure, because receptor partial activation usually avoids overstimulation and also minimizes desensitization. At present, partial agonists are obtained almost exclusively by screening numerous newly-synthesized compounds, and little is known about the rational design of partial agonists with desired potencies and maximum activities. It is proposed in this study that a proper covalent attachment of a receptor full agonist to an antagonist (competitive or non-competitive) of the same receptor type may form a hybrid compound with a reduced maximum activity. In theory, the potency (EC50 value) and the reduced maximum activity of such an agonist-antagonist hybrid are predictable, based on the receptor binding affinities of the incorporated agonist and antagonist. The agonist-noncompetitive antagonist hybrids produce bell-shaped concentration-response curves, whereas the agonist-competitive antagonist hybrids produce concentration-response curves with reduced but plateaued maximum responses. The agonist-competitive antagonist hybrids can be very useful for therapeutic purposes because they enable us to stably activate a specific type of receptor at desired submaximal set-points. In this study, it is postulated that some partial agonists may also contain both agonistic and antagonistic moieties, analogous to the proposed hybrid compounds. This hypothesis is supported by data from modeling studies showing that several unique pharmacological characteristics of known partial agonists exactly match the projected features of the agonist-antagonist hybrid compounds. Modeling studies based on the hybrid compound model also explain why the reduced maximum response elicited by some partial agonists can be increased or even fully restored in the presence of spare receptors. As indicated by modeling studies, a reduced maximum activation of receptors may, at least in some cases, not result from a partial activation of each individual receptor being occupied by the partial agonist, but rather may be due to a reduced maximal receptor occupancy by the agonistic moiety in the co-presence of an antagonistic moiety. The agonist-antagonist hybrid proposed in this study not only enhances our understanding of the possible structural requirements and rational design of receptor partial agonists, but it also enhances our understanding of the possible molecular basis of receptor partial activation. This new model also provides an alternative mathematical framework for modeling partial agonist data.

Binding, Competitive↗
PubMed1995

The binding modes of a rationally designed photoactivated DNA nuclease determined by NMR.

The complex between the rationally designed synthetic DNA cleaving agent netropsin-diazene and the double-stranded DNA oligomer 5'-CGCAAAGGC-3'.5'-GCCTTTTGCG-3' was characterized by two-dimensional NMR spectroscopy in solution. Photolysis of netropsin-diazene bound to DNA generates a trimethylenemethane diradical intermediate that induces single-strand breaks in the DNA. The pi-diyl trimethylenemethane based compounds are a new class of DNA nucleases. We tested the following design criteria: (i) binding of the diazene and subsequent reactive diyl to the DNA, (ii) sequence selectivity in the ligand binding and (iii) prevention of diyl dimerization. Sixteen NOE derived ligand-DNA distance restraints were used to obtain the energy minimized model of the complex. The ligand is bound to the minor groove of the oligomer with the diazene at the 5' end of the A-tract in the predominant conformation of the complex. This form of the complex exchanges with a minor conformation in which the ligand is in the opposite orientation. The DNA maintains a B-form structure. Netropsin-diazene has fulfilled all of the design criteria, binding to the DNA duplex studied in the minor groove of the central AAAA tract in a 1:1 mode, preventing diyl dimerization and other side reactions from occurring.

Base Sequence↗
PubMed1991

Rational design of purification processes for recombinant proteins.

Recent developments in the rational design of purification processes for recombinant proteins are discussed. A review of the main issues involved in process design for protein separation and purification is presented with particular emphasis on the challenges posed by recombinant proteins. This includes physicochemical characterization of target protein and main contaminants, the use of rigorous mathematical modeling and process simulation as well as the development of an expert system and the application of this technology for optimization and design of large scale processes. An expert system for selection of optimal protein separation sequences will give the user a number of alternatives chosen on the basis of extensive data back-up on proteins and unit operations.

Biotechnology↗
PubMed1999

New approaches to rational drug design.

Rational drug design has emerged as a powerful technique. In this review, three new developments in rational drug design are explored. These developments include new methods to find binding sites for small molecules on the surface of a protein, the suggestion that the protein environment may change the shape of a protein sufficiently to alter drug design, and the use of data emerging from structural genomics in drug design. Although these are three new and distinct areas, the insights derived from these studies suggest a reason for the observation that similar drugs do not always bind to a protein in the same manner.

Binding Sites↗
PubMed2006

Rational design of hydrogels for tissue engineering: impact of physical factors on cell behavior.

When designing suitable biomaterials for tissue-engineering applications, biological and chemical parameters are frequently taken into account, while the equally important physical design variables have often been neglected. For a rational design of biomaterials, however, all variables influencing cell function and tissue morphogenesis have to be considered. This review will stress the development of cross-linked hydrogels and outline the impact of their physical properties on cell function and tissue morphogenesis. In the first part, the principles of cellular mechanosensitivity, as well as the influence of substrate mechanics on cell behavior, will be discussed. Afterwards, methods to characterize the mechanical properties of biomaterials will be presented. The subsequent chapters will address hydrogels that allow for the control of their physical qualities followed by a discussion of their use in tissue-engineering applications.

Biocompatible Materials↗
PubMed2005

Possibilities and limitations in the rational design of modified peptides for T cell mediated immunotherapy.

Therapeutic intervention in experimental autoimmune diseases by modulation of the T cell mediated autoimmune response has been accomplished in the past using altered peptide ligands (APLs). These peptides are usually created by applying alterations to the T cell epitope recognized by the autoaggressive T cells. In this study, we investigated whether it was possible to design APLs in a rational way, using knowledge of molecular interaction in the MHC-peptide-T cell receptor (TCR) complex, for the therapeutic intervention in experimental autoimmune encephalomyelitis (EAE). Additionally, the value of peptidomimetic modification and alterations based on posttranslational modifications for the design of APLs was examined. Based on a molecular model of the MHC-peptide complex, the T cell receptor contact residues were identified and selected alterations were applied. The designed APLs were tested for MHC binding capacity, T cell recognition, blocking of the autoreactive T cell response, immunogenicity, encephalitogenicity, and therapeutic activity. Based on the results of the in vitro assays, it was expected that some of our APLs would be able to modulate EAE. Nevertheless, none of these APLs displayed clear therapeutic activity in vivo. Thus, rational design of modified peptides for immunotherapy has to await further insights into the relationships between structure and peptide/peptidomimetic induced T cell activation, and until that, there is no possibility to take advantage of the tailor made origin of peptidomimetics.

Amino Acid Sequence↗
PubMed2004

From toxin to adjuvant: the rational design of a vaccine adjuvant vector, CTA1-DD/ISCOM.

Mucosally active vaccine adjuvants which will prime a full range of local and systemic immune responses against defined antigenic epitopes are much needed. Cholera toxin (CT) and lipophilic immune stimulating complexes (ISCOMs) containing Quil A can both act as adjuvants for orally administered antigens, but through separate pathways, as evidenced by the dependence on IL-12 for the effect of ISCOMs, whereas CT is independent of this cytokine. Unfortunately the toxicity of CT and recent findings of accumulation of CT in the olfactory nerve and bulb after intranasal administration precludes the clinical use of CT. However, we have been successful in separating the adjuvant and toxic effects of CT, by constructing a gene fusion protein, CTA1-DD, that combines the enzymatically active CTA1-subunit with a B cell targeting moiety, D, derived from Staphylococcus aureus protein A. The present review gives a background to mucosal immunization and the use of -adjuvants in general, followed by a description of a strategy to rationally design a vaccine adjuvant vector that fulfils the criteria of targeting and immunomodulating innate immunity in order to boost a strong adaptive immune response. We have combined CTA1-DD and ISCOMs into a new highly promising vaccine adjuvant vector, CTA1-DD/ISCOMs. The combined vector is immunogenic when given by the subcutaneous, oral or nasal routes, inducing strong cell--mediated and humoral immune responses, including local mucosal IgA. It requires the ADP ribosylating property of the CTA1-enzyme and the effect of the combined vector greatly exceeded the effect of either ISCOMs or CT used alone. Antigens could be incorporated into or just admixed with the new vector. Thus, we have demonstrated that rationally designed vectors consisting of CTA1-DD and ISCOMS may provide a novel strategy for the generation of potent and safe mucosal vaccines.

Adjuvants, Immunologic↗
PubMed2005

Semi-rational approaches to engineering enzyme activity: combining the benefits of directed evolution and rational design.

Many research groups successfully rely on whole-gene random mutagenesis and recombination approaches for the directed evolution of enzymes. Recent advances in enzyme engineering have used a combination of these random methods of directed evolution with elements of rational enzyme modification to successfully by-pass certain limitations of both directed evolution and rational design. Semi-rational approaches that target multiple, specific residues to mutate on the basis of prior structural or functional knowledge create 'smart' libraries that are more likely to yield positive results. Efficient sampling of mutations likely to affect enzyme function has been conducted both experimentally and, on a much greater scale, computationally, with remarkable improvements in substrate selectivity and specificity and in the de novo design of enzyme activities within scaffolds of known structure.

Combinatorial Chemistry Techniques↗
PubMed1992

Rational design of purification processes for recombinant proteins.

This paper discusses the elements important for rational design of purification processes for recombinant proteins. Main issues involved in selection of operations and process design are reviewed with particular emphasis on the challenges posed by recombinant proteins. This includes thermodynamic characterization of target protein and main contaminants, use of correlations and of expert knowledge for the development of an expert system for optimization and design (selection) of separation and purification (chromatographic) processes. The main deficiency in accurate information for rational process selection is in that required for high-resolution chromatographic processes. The authors show that a database with detailed information on properties of the main contaminants present in the fermentation streams of usual recombinant protein sources can be integrated to an expert system with an open architecture. This will allow more precise selection of unit operations for the design of protein purification processes.

Animals↗
PubMedDate not supplied

Synthesis and screening of a rationally designed combinatorial library of affinity ligands mimicking protein L from Peptostreptococcus magnus.

Rational design and combinatorial chemistry were utilized to search for lead protein L (PpL) mimetics for application as affinity ligands for the purification of antibodies and small fragments, such as Fab and scFv, and as potential diagnostic or therapeutic agents. Inspection of the key structural features of the complex between PpL and human Fab prompted the de novo design and combinatorial synthesis of a 169-membered solid-phase ligand library, which was assessed for binding to human IgG and subsequent selectivity for the Fab fragment. Eight ligands were selected, chemically characterized and compared with a commercial PpL-adsorbent for binding pure immunoglobulin fractions. The most promising lead, ligand 8/7, when immobilized on an agarose support, behaved in a similar fashion to PpL in isolating Fab fragments from papain digests of human IgG to a final purity of 97%.

Affinity Labels↗
PubMed1994

The rational design of amino acid sequences by artificial neural networks and simulated molecular evolution: de novo design of an idealized leader peptidase cleavage site.

A method for the rational design of locally encoded amino acid sequence features using artificial neural networks and a technique for simulating molecular evolution has been developed. De novo in machine design of Escherichia coli leader peptidase (SP1) cleavage sites serves as an example application. A modular neural network system that employs sequence descriptions in terms of physicochemical properties has been trained on the recognition of characteristic cleavage site features. It is used for sequence qualification in the design cycle, representing the sequence fitness function. Starting from a random sequence several cleavage site sequences were generated by a simulated molecular evolution technique. It is based on a simple genetic algorithm that takes the quality values calculated by the artificial neural network as a heuristic for inductive sequence optimization. Simulated in vivo mutation and selection allows the identification of predominant sequence positions in Escherichia coli signal peptide cleavage site regions (positions -2 and -6). Various amino acid distance maps are used to define metrics for the step size of mutations. Position-specific mutability values indicate sequence positions exposed to high or low selection pressure in the simulations. The use of several distance maps leads to different courses of optimization and to various idealized sequences. It is concluded that amino acid distances are context dependent. Furthermore, a method for identification of local optima during sequence optimization is presented.

Algorithms↗
PubMed2002

alpha(1)-Adrenoceptor antagonists. Rational design, synthesis and biological evaluation of new trazodone-like compounds.

A rational design approach has been applied to synthesize a novel class of compounds with affinity for alpha(1) adrenergic receptors (AR). Molecular structures are characterized by a benzimidazolylpyridazinone or an imidazolylpyridazinone moiety, an original fragment in the field of the arylpiperazine compounds with alpha(1)-AR blocking properties. A 1.1 nM affinity toward alpha(1)-AR was found for compound 3, the most active of this series.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2004

Prevention of Alzheimer's disease-associated Abeta aggregation by rationally designed nonpeptidic beta-sheet ligands.

A new concept is introduced for the rational design of beta-sheet ligands, which prevent protein aggregation. Oligomeric acylated aminopyrazoles with a donor-acceptor-donor (DAD) hydrogen bond pattern complementary to that of a beta-sheet efficiently block the solvent-exposed beta-sheet portions in Abeta-(1-40) and thereby prevent formation of insoluble protein aggregates. Density gradient centrifugation revealed that in the initial phase, the size of Abeta aggregates was efficiently kept between the trimeric and 15-meric state, whereas after 5 days an additional high molecular weight fraction appeared. With fluorescence correlation spectroscopy (FCS) exactly those two, i.e. a dimeric aminopyrazole with an oxalyl spacer and a trimeric head-to-tail connected aminopyrazole, of nine similar aminopyrazole ligands were identified as efficient aggregation retardants whose minimum energy conformations showed a perfect complementarity to a beta-sheet. The concentration dependence of the inhibitory effect of a trimeric aminopyrazole derivative allowed an estimation of the dissociation constant in the range of 10(-5) m. Finally, electrospray ionization mass spectrometry (ESI-MS) was used to determine the aggregation kinetics of Abeta-(1-40) in the absence and in the presence of the ligands. From the comparable decrease in Abeta monomer concentration, we conclude that these beta-sheet ligands do not prevent the initial oligomerization of monomeric Abeta but rather block further aggregation of spontaneously formed small oligomers. Together with the results from density gradient centrifugation and fluorescence correlation spectroscopy it is now possible to restrict the approximate size of soluble Abeta aggregates formed in the presence of both inhibitors from 3- to 15-mers.

Alzheimer Disease↗
PubMed1997

A strategy for rational design of fully synthetic glycopeptide conjugate vaccines.

The present study describes a strategy to rationally design fully synthetic glycopeptide conjugate vaccines. Glycopeptide immunogens were constructed by coupling synthetic oligosaccharides comprising repeating units of synthetic 3-beta-D-ribose-(1-1)-D-ribitol-5-phosphate (sPRP) to synthetic peptides containing potent T-helper cell determinants and B-cell epitopes of the Haemophilus influenzae type b (Hib) outer membrane proteins (OMPs) P1, P2, and P6. Rabbit immunogenicity studies revealed that some of these fully synthetic glycoconjugates were capable of eliciting high titers of both anti-PRP and anti-OMP immunoglobulin G antibodies. In addition, we systematically investigated the factors which could influence their immunogenicity. We observed that the magnitude of the anti-PRP antibody response markedly depended on the relative spatial orientation of sPRP and T-cell epitopes, the anti-PRP antibody response was enhanced when a multiple antigenic peptide was used as a carrier, the anti-PRP antibody response was optimal for three PRP repeating units, and lipidation of peptide-PRP conjugates had a minimal effect on the magnitude of the anti-PRP antibody response. The results of this study clearly demonstrate that coupling a carbohydrate hapten to a peptide can provide T-cell help and convert it into a T-cell-dependent antigen. The antisera raised against these conjugates were also found to be protective against Hib infection in the infant rat model of bacteremia.

Amino Acid Sequence↗
PubMed2005

Rational design of dental materials using computational chemistry.

One of our primary research emphases is the rational design of biomaterials. In this effort we apply a combination of theoretical and experimental approaches, both of which contribute directly to the completion of such a project. Computational chemistry has achieved routine status in modern chemical investigations, and the state-of-the-art is briefly summarized. In such a difficult endeavor as the systematic development of biomaterials, computational chemistry is a natural partner for traditional chemists. Herein, we describe several successful applications of this synergy to the design of dental biomaterials. These include reactivity modeling, sensitization, and density. We also report preliminary progress of polymerization volume change experiments on epoxides that have been specifically designed to provide standardized results for computational analysis.

Combinatorial Chemistry Techniques↗
PubMed2000

Treatment of experimental allergic encephalomyelitis (EAE) by a rationally designed cyclic analogue of myelin basic protein (MBP) epitope 72-85.

In this report the rational design, synthesis and pharmacological properties of an amide-linked cyclic antagonist analogue of the guinea pig myelin basic protein epitope MBP(72-85) are described. Design of the potent cyclic analogue was based on 2D NOESY nuclear magnetic resonance and molecular dynamics studies carried out in the linear antagonist Ala81MBP(72-85). The cyclic antagonist completely prevented the induction of experimental allergic/autoimmune encephalomyelitis when coinjected with linear and cyclic agonist analogues MBP(72-85) and cyclo(2-9)MBP(72-85).

Animals↗
PubMed2005

Rational design of platinum(IV) compounds to overcome glutathione-S-transferase mediated drug resistance.

A rationally designed Pt(IV) anticancer compound is described, employing the novel concept of tethering an inhibitor of glutathione-S-transferase, an enzyme associated with Pt-based drug-resistance, to cisplatin. Its enzyme inhibition activity, investigated using spectrophotometric and mass spectrometry-based techniques, and cytotoxic profile in resistant cancer cells are described.

Cell Line, Tumor↗