Using "rationally designed drugs" rationally.
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Antineoplastic Agents↗
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Rational design, analysis, and potential utility of GM-CSF antagonists.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an important cytokine involved in many immune and inflammatory processes and is believed to act in the early stages of immune responses. GM-CSF stimulates antigen-presenting cells, enhancing antigen presentation and inducing macrophage tumoricidal activity. GM-CSF binds to specific cellular receptors that are potential targets for pharmacological design. Rational design of small-molecule mimics is an important approach to pharmacophore design. One of the strategies in the development of small-molecular mimics of larger polypeptyde ligands is analysis of alternative ligands that bind the same site as does the native ligand. Molecular studies of GM-CSF-receptor interactions have led to the development of interaction site analogs and the development of an "anti-anti-GM-CSF" recombinant antibody (rAb) analog of a site on GM-CSF important for biological activity and receptor binding. This rAb and a peptide derived from the rAb first complementarity determining region (CDR) sequence bind to a monoclonal anti-GM-CSF antibody that mimics the GM-CSFR alpha chain, compete with GM-CSF for binding to GM-CSF receptor alpha chain (GM-CSFR alpha), and are specific biological antagonists. Molecular modeling of the rAb suggests structural similarity with a site previously implicated in GM-CSF binding to the GM-CSFR alpha. Two cyclic peptides, 1785 and 1786, also were developed on the basis of structural analysis of the GM-CSF region mimicked by anti-anti-GM-CSF recombinant antibody (rAb) 23.2. These peptides were designed to mimic structurally the positions of specific residues on the B and C helicies of human GM-CSF implicated in receptor binding and bioactivity. Both 1785 and 1786 were recognized specifically by polyclonal anti-GM-CSF antibody. 1786 also competitively inhibited binding of GM-CSF to the GM-CSF receptor and demonstrated antagonist bioactivity, as shown by its reversal of GM-CSF's ability to inhibit apoptosis of the GM-CSF-dependent cell line MO7E. These studies support the role of residues on the GM-CSF B and C helicies in receptor binding and bioactivity and suggest strategies for mimicking binding sites on four-helix bundle proteins with cyclic peptides.
Amino Acid Sequence↗
Knowledge of the proposed chemical mechanism of action and cytochrome p450 metabolism of antimalarial trioxanes like artemisinin allows rational design of new antimalarial peroxides.
Evidence is reviewed elucidating the mechanism of iron-induced triggering of antimalarial trioxanes. As prodrugs, trioxanes undergo homolytic, inner-sphere, reductive cleavage by ferrous iron to form sequentially oxy radicals, carbon radicals, high-valent iron-oxo species, epoxides, aldehydes, and dicarbonyl compounds. One or more of these reactive intermediates and neutral alkylating agents likely kill the malaria parasites. Several new, orally active antimalarial peroxides have been designed rationally based on this fundamental mechanistic paradigm. Incorporating metabolism-blocking substituents also provides some new, potent, semi-synthetic artemisinin derivatives.
Animals↗
Rational design of thermostable lactate oxidase by analyzing quaternary structure and prevention of deamidation.
Our current knowledge of protein unfolding is overwhelmingly related to reversible denaturation. However, to engineer thermostable enzymes for industrial applications and medical diagnostics, it is necessary to consider irreversible denaturation processes and/or the entire quaternary structure. In this study we have used lactate oxidase (LOD), which is employed in lactic acid sensors, as a model example to design thermostable variants by rational design. Twelve mutant proteins were tested and one of them displayed a markedly greater thermostability than all the mutants we had previously obtained by random mutagenesis. This mutant was designed so as to strengthen the interaction between the subunits and stabilize the quaternary structure. Since LOD is difficult to crystallize, its three-dimensional structure remains unknown. This study shows that it is possible to carry out rational design to improve thermostability using a computer-aided quaternary structure model based on the known tertiary structure of a related protein. Critical factors required for increasing the thermal stability of proteins by rational design, where the 3-D structure is not available, are discussed.
Amides↗
Targeting JAK3 and BTK tyrosine kinases with rationally-designed inhibitors.
Multifunctional rational drug design of protein tyrosine kinases inhibitors allows a potent drug to be utilized to treat more than one disease for greater patient benefits. Many protein tyrosine kinases (PTK), including Janus kinase 3 (JAK3) and Bruton's tyrosine kinase (BTK), have been identified as potential drug targets to treat diverse diseases including cancer and disorders of the immune system. Here we review advances in JAK3 and BTK inhibitors and describe the therapeutic potential of these potent agents in the clinical setting.
Agammaglobulinaemia Tyrosine Kinase↗
Computer-assisted rational design of immunosuppressive compounds.
We describe the rational design of immunosuppressive peptides without relying on information regarding their receptors or mechanisms of action. The design strategy uses a variety of topological and shape descriptors in combination with an analysis of molecular dynamics trajectories for the identification of potential drug candidates. This strategy was applied to the development of immunosuppressive peptides with enhanced potency. The lead compounds were peptides, derived from the heavy chain of HLA class I, that modulate immune responses in vitro and in vivo. In particular, a peptide derived from HLA-B2702, amino acids 75-84 (2702.75-84) prolonged skin and heart allograft survival in mice. The biological activity of the rationally designed peptides was tested in a heterotopic mouse heart allograft model. The molecule predicted to be most potent displayed an immunosuppressive activity approximately 100 times higher than the lead compound.
Animals↗
Conformationally constrained CCK8 analogues obtained from a rationally designed peptide library as ligands for cholecystokinin type B receptor.
A library of 14 cyclic peptide analogues derived from the octapeptide C-terminal sequence of the human cholecystokinin hormone (CCK(26-33), or CCK8) was designed, synthesized, and characterized. The 14 peptide analogues were rationally designed to specifically interact with the CCK type B receptor (CCK(B)-R) on the basis of the structure of the bimolecular complex between CCK8 and the third extracellular loop of CCK(B)-R, namely CCK(B)-R(352-379). The rational design of new ligands for CCK(B)-R has relied on stabilization by cyclic constraints of the structural motifs that bring the key residues of the ligand (especially Trp 30, Met 31, and Phe 33) in the proper spatial orientation for optimal interaction with the receptor. The binding affinity of the new ligands for CCK(B)-R was assessed by displacement experiments of (111)In-radiolabeled CCK8 in cells that overexpress the CCK(B) receptor. The new ligands generally showed binding affinities lower than that of parent CCK8, with the best compounds having IC50 values around 10 microM. Structure-activity relationship data show that preservation of the Trp 30-Met 31 motif is essential and that the Phe 33 side chain must be present. NMR conformational studies of the compound with maximal binding affinity (cyclo-B11, IC50=11 microM) in DPC micelles shows that this compound presents a turn-like conformation centered at the Trp 30-Met 31 segment, as planned by rational design. Such a conformation is stabilized by its interaction with the micelle rather than by the cyclic constraint.
Cholecystokinin↗
Rational design of porous titanophosphates.
To rationally design new nanoporous materials based on titanophosphates, a small library of titanium phosphate crystalline nanoporous compounds has been build up and its compounds have been investigated by X-ray diffraction and by in- and ex-situ NMR. The main trends of the unusual titanium solution chemistry, of the prenucleation building units and of their assembling have been established. The classical trial and error strategy can therefore be replaced by a better control of the steps leading to the final targeted network.
Journal Article↗
Rational design of polymerase inhibitors as antiviral drugs.
Almost all viruses have polymerases which are suitable targets for antiviral drugs. The development of selective polymerase inhibitors started with screening of compounds in virus-infected cell cultures and the mechanism of action was investigated once an inhibitor had been found. Especially nucleoside analogs were screened as their triphosphates were potential substrates for polymerases. However, the stepwise phosphorylation by cellular, and sometimes viral, kinases to the active triphosphate prevented a truly rational design of polymerase inhibitors. Nucleotide analogs offers a type of compounds which could be designed in a more rational way than nucleoside analogs since the first, most selective, phosphorylation step is eliminated in the path to the active inhibitor. The development of pyrophosphate analogs made rational design possible since these compounds act directly on the viral enzyme, but the room for structural variation was limited. The non-nucleoside HIV reverse transcriptase inhibitors are direct inhibitors and can thus be designed in a truly rational way by use of structure information on the enzyme-inhibitor complex by use of X-ray and NMR. This rational design of allosteric inhibitors is also being used in the development of inhibitors to other viral polymerases.
Antiviral Agents↗
Towards the rational design of cereal starches.
A major challenge in cereal biotechnology is to achieve the rational design of renewable polymers to meet specific requirements for improving human health, nutrition, and food quality, to increase the energy supply, and to provide safer and more profitable industrial inputs. The field of starch synthesis research has advanced at a rapid pace over the past decade, and many core observations about the pathway are well established over a range of species. Owing to the complexity of the starch-synthesis process, in which suites of enzymes act at the interface between soluble and insoluble phases, the rational design of starch granules with specific functionality is still in its infancy. Our fundamental biochemical knowledge of starch biosynthesis has recently advanced, and this new information could be exploited to create novel variability in carbohydrate polymers in cereal grains. We propose two strategies for moving more rapidly towards truly rational design of starch. First, the focusing of fundamental research on processes that are involved in the regulation of starch synthesis and granule assembly. Second, the development of iterative strategies, exploiting new molecular genetics tools, to screen for desired properties in high-throughput systems.
Biotechnology↗
A rationally designed agonist antibody fragment that functionally mimics thrombopoietin.
By using rational design, antibody fragments (Fabs) that mimic thrombopoietin (TPO) were created. A peptide with cMpl receptor-binding capability was grafted into different complementarity-determining regions of a fully human Fab scaffold. Functional presentation of the peptide was optimized by using phage display and cell-based panning. Select antibodies and fragments containing two grafted peptides were assayed for their ability to stimulate the cMpl receptor in vitro. Several candidates demonstrated agonist activity in an in vitro cMpl receptor signaling reporter assay, including Fab59, which was estimated to be equipotent to TPO. Fab59 additionally was able to effectively stimulate platelet production in normal mice. These rationally designed mimetic Fabs may provide a therapeutic intervention for thrombocytopenia while avoiding the potential generation of neutralizing antibodies to endogenous TPO. Furthermore, this study demonstrates a method by which short-lived linear peptides with binding activity may be converted to more stable and potent agonists capable of activating cell surface receptors.
Animals↗
Rational design of aromatic polyketide natural products by recombinant assembly of enzymatic subunits.
Recent advances in understanding of bacterial aromatic polyketide biosynthesis allow the development of a set of design rules for the rational manipulation of chain synthesis, reduction of keto groups and early cyclization steps by genetic engineering. The concept of rational design is illustrated by the preparation of Streptomyces strains that produce two new polyketides by expression of combinations of appropriate enzymatic subunits from naturally occurring polyketide synthases. The potential for generating molecular diversity within this class of molecules by genetic engineering is enormous.
Genetic Engineering↗
Inhibition of 2,3-oxidosqualene: beta-amyrin-cyclase, S-adenosyl-L-methionine: cycloartenol C-24-methyltransferase and cycloeucalenol: obtusifoliol isomerase by rationally designed molecules containing a tertiary amine function.
25-Azacycloartanol (I), 2-aza-2-dihydrosqualene (II) and Tridemorph (2,6-dimethyl-N-tridecylmorpholine) (III) are potent inhibitors of higher plant sterol biosynthesis. The first two molecules have been designed using rational enzymological concepts. I, II and III were shown to inhibit the S-adenosyl-L-methionine: cycloartenol C-24-methyltransferase, the 2,3-oxidosqualene: beta-amyrin-cyclase and the cycloeucalenol: obtusifoliol isomerase, respectively. Inhibition was demonstrated either in vivo on bramble cell suspensions or in vitro on microsomes from maize seedlings. Each inhibitor has been shown to have a high affinity for its presumed enzymic target and only negligible inhibitory action on the other two enzymes. The applications of these results to further physiological studies are discussed.
Chemical Phenomena↗
Comparison of in vivo selection and rational design of heterodimeric coiled coils.
To investigate how electrostatic interactions restrict the associations of coiled coils, we improved a heterodimeric coiled coil (WinZip-A1B1) by in vivo selection and, alternatively, by rational design. Selection from libraries encoding variable edge (g and e) residues enriched g/e' ion pairs, but the optimum selected heterodimers unexpectedly retained two predicted repulsive g/e' pairs. The best genetically selected heterodimer displayed similar thermodynamic stability and specificity as a rationally designed dimer with predicted ion pairs at all edge positions. This rationally designed pair, however, was less effective than the best genetically selected pair in mediating dimerization in vivo. Thus, the effects of predicted charge pairs depend on sequence context, and complementary charges at the edge positions rationalize only a fraction of the sequences that form stable, specific coiled coils.
Cell Division↗
Rationally designed allosteric variants of hammerhead ribozymes responsive to the HIV-1 Tat protein.
Hammerhead ribozymes that are subject to allosteric control by small molecule and oligonucleotide effectors have been reported recently. Rational design has been an effective strategy for the creation of these ribozymes, which incorporate structurally interdependent hammerhead motifs and effector-binding sequences. In this paper we report the rational design of the first protein-responsive allosteric ribozymes that are regulated by the HIV-1 Tat. The TAR-Tat interaction of HIV-1 has the interesting feature that both Tat and arginine are able to bind to and bring about comparable conformational changes in the TAR loop. Here we describe the construction of two classes of TAR-modified hammerhead ribozymes and their response to Tat protein and to its derivatives. Instances of both allosteric activation and inhibition were found. Interestingly, the activation response was stimulated by both Tat and argininamide while the inhibitory response was stimulated by Tat and by its derivative peptide, ADP1, but not by argininamide. Overall, the extent of allosteric response in our ribozymes was modest relative to those reported for ribozymes with small molecule effectors. Future work utilizing combinatorial approaches along with elements of rational design should reveal the means by which highly efficient, protein-mediated allostery of ribozymes may be achieved.
Allosteric Regulation↗
Protein surface recognition by rational design: nanomolar ligands for potassium channels.
The rational design and development of four-fold symmetrical ligands for potassium channels is described.
Amino Acid Sequence↗
Carbohydrate mimotopes in the rational design of cancer vaccines.
The task of rationally designing vaccines that can effectively impact on the survival of cancer patients remains challenging. Monoclonal antibodies and T cell receptors have proven to be viable templates for the application of pharmacophore design principles to develop antigens and immunogens as these immune system molecules recognize a variety of sequentially and structurally unrelated ligands. This structural information combined with immunological assessment has contributed to the development of strategies to elicit effective humoral and cellular responses to cancer cells. Understanding the structural requirements for antibody and T cell recognition provides a basis for identifying potentially new sets of immunogens that may have both fundamental immunological and clinical value. Here we review the structural concepts and approaches used in vaccine design applications that illustrate the value and limitations of using chemical (peptide libraries) and immunological information to define novel peptide immunogens that function as mimotopes to generate immune responses targeting tumor associated carbohydrate antigens.
Adenocarcinoma↗
The pursuit of optimal outcomes in cancer therapy in a new age of rationally designed target-based anticancer agents.
There have been extraordinary advances in anticancer therapy over the last few decades, particularly for patients with relatively uncommon malignancies, largely because of the advent of nonspecific cytotoxic chemotherapeutics. Although these agents have also brought improved outcomes for patients with many of the more common solid cancers, it is clear that the point of 'diminishing return' has been reached. The recent development of a plethora of rationally designed target-based anticancer agents has opened up new opportunities and extraordinary therapeutic challenges. Since these agents appear primarily to target malignant cells, they can be expected to be less toxic at clinically effective doses than the cytotoxic agents. Among the various types of rationally designed target-based agents are those that target strategic facets of cell growth signal transduction, angiogenesis, metastasis and cell cycle regulation. While the primary therapeutic benefit of these agents is expected to be decreased tumour growth, evidence suggests that objective tumour responses may also be achieved. However, because of their potentially cytostatic properties, the clinical efficacy of such biologically based agents may not be readily demonstrable with traditional phase I and II study methodologies. Additionally, their dose-toxicity relationships are likely to be less steep than those of the nonspecific cytotoxic agents, thereby rendering such concepts as the maximum tolerated dose less meaningful than alternatives such as the optimal biological dose or the biologically effective dose. Those end-points generally considered, both from a regulatory and clinical viewpoint, to be of secondary importance in trials of cytotoxic agents, such as time to disease progression, disease-related symptoms and quality of life, may evolve into primary end-points. Present findings from preclinical studies suggest that the development, evaluation and general clinical use of rationally designed target-based anticancer agents will require a radical departure from the traditional paradigms if the full potential of these new therapies is to be exploited.
Antineoplastic Agents↗