Janice M. Kerr

Bio: Janice M. Kerr is an academic researcher from Chiron Corporation. The author has contributed to research in topics: Peptoid & Monomer. The author has an hindex of 12, co-authored 17 publications receiving 2955 citations.

Efficient method for the preparation of peptoids [oligo(N-substituted glycines)] by submonomer solid-phase synthesis

Abstract: Oligomers of N-substituted glycines, or “peptoids“, represent a new class of polymers (Figure 1) that are not found in nature, but are synthetically accessible and have been shown to possess significant biological activity and proteolytic stability.’ We present here an efficient, automated solid-phase method for the synthesis of oligo(N-substituted glycines) (NSGs) which is general for a wide variety of side-chain substituents and allows the rapid synthesis of molecules of potential therapeutic interest. The original method’ for the synthesis of oligomeric NSGs is analogous to standard solid-phase methods for peptide synthesis. Specifically, the carboxylate of Nu-Fmoc-protected (and sidechain-protected) NSGs is activated and then coupled to the secondary amino group of the resin-bound peptoid chain. Removal of the Fmoc group is then followed by addition of the next monomer. Thus, oligomeric NSGs have been treated as condensation homopolymers of N-substituted glycine. A disadvantage of this approach, however, is the necessity of preparing suitable quantities of a diverse set of protected N-substituted glycine monomers. In the method presented here, each N-substituted glycine monomer is assembled from two readily available “submonomers” in the course of extending the NSG polymer (Scheme I). Thus, oligomeric NSGs can also be considered to be alternating condensation copolymers of a haloacetic acid and a primary amine. As in the original method, the direction of polymer synthesis with the submonomers occurs in the carboxy to amino direction. The solid-phase assembly of each monomer, in the course of controlled polymer formation, eliminates the need for N*-protected monomers, as only reactive side-chain functionalities need to be protected. The a-haloacetyl submonomer is common to all cycles of chain extension. Moreover, each RNH2 submonomer is simpler in structure and many are commercially available; thus, oligo(NSG) synthesis is dramatically simplified. The preparation of NSG oligomers by the submonomer method2

Discovery of nanomolar ligands for 7-transmembrane G-protein-coupled receptors from a diverse N-(substituted)glycine peptoid library.

Abstract: Screening a diverse, combinatorial library of ca. 5000 synthetic dimer and trimer N-(substituted)glycine "peptides" yielded novel, high-affinity ligands for 7-transmembrane G-protein-coupled receptors. The peptoid library was efficiently assembled using readily available chemical building blocks. The choice of side chains was biased to resemble known ligands to 7-transmembrane G-protein-coupled receptors. All peptides were screened in solution-phase, competitive radioligand-binding assays. Peptoid trimer CHIR 2279 binds to the alpha 1-adrenergic receptor with a Ki of 5 nM, and trimer CHIR 4531 binds to the mu-opiate receptor with a Ki of 6 nM. This represents the first example of the discovery of high-affinity receptor ligands from a combinatorial library of non-natural chemical entities.

Comparison of the proteolytic susceptibilities of homologous L-amino acid, D-amino acid, and N-substituted glycine peptide and peptoid oligomers

Abstract: A series of homologous L-amino acid, D-amino acid, and both parallel and anti-parallel (retro) sequence N-substituted glycine peptide and peptoid oligomers were prepared and incubated with a series of enzymes representative of the major classes of proteases. Each respective L-amino acid containing peptide sequence was readily cleaved by the appropriate enzyme, namely Ac-L-ala-L-leu-L-phe-L-ala-L-leu-L-arg-NH2 by chymotrypsin, Ac-L-ala-L-ala-L-ala-L-leu-L-phe-L-arg-NH2 by elastase, Ac-L-ala-L-phe-L-glu-L-leu-L-ala-L-ala-NH2 by papain, Z-L-ala-L-his-L-phe-L-phe-L-arg-L-leu-NH2 by pepsin, Ac-L-phe-L-ala-L-arg-L-ala-L-arg-L-asp-NH2 by trypsin, and Ac-L-ala-L-tyr-Lala-L-phe-OH for carboxypeptidase A. In contrast, equivalent D-amino acid containing and N-substituted glycine containing oligomers were cleaved minimally or not at all by the respective enzymes. The N-substituted glycine peptoids represent a new class of combinatorial diversity for lead discovery with improved pharmaceutical characteristics relative to L-amino acid containing peptides. © 1995 Wiley-Liss, Inc.

Target-oriented and diversity-oriented organic synthesis in drug discovery.

Abstract: Modern drug discovery often involves screening small molecules for their ability to bind to a preselected protein target. Target-oriented syntheses of these small molecules, individually or as collections (focused libraries), can be planned effectively with retrosynthetic analysis. Drug discovery can also involve screening small molecules for their ability to modulate a biological pathway in cells or organisms, without regard for any particular protein target. This process is likely to benefit in the future from an evolving forward analysis of synthetic pathways, used in diversity-oriented synthesis, that leads to structurally complex and diverse small molecules. One goal of diversity-oriented syntheses is to synthesize efficiently a collection of small molecules capable of perturbing any disease-related biological pathway, leading eventually to the identification of therapeutic protein targets capable of being modulated by small molecules. Several synthetic planning principles for diversity-oriented synthesis and their role in the drug discovery process are presented in this review.

A field guide to foldamers.

Abstract: III. Foldamer Research 3910 A. Overview 3910 B. Motivation 3910 C. Methods 3910 D. General Scope 3912 IV. Peptidomimetic Foldamers 3912 A. The R-Peptide Family 3913 1. Peptoids 3913 2. N,N-Linked Oligoureas 3914 3. Oligopyrrolinones 3915 4. Oxazolidin-2-ones 3916 5. Azatides and Azapeptides 3916 B. The â-Peptide Family 3917 1. â-Peptide Foldamers 3917 2. R-Aminoxy Acids 3937 3. Sulfur-Containing â-Peptide Analogues 3937 4. Hydrazino Peptides 3938 C. The γ-Peptide Family 3938 1. γ-Peptide Foldamers 3938 2. Other Members of the γ-Peptide Family 3941 D. The δ-Peptide Family 3941 1. Alkene-Based δ-Amino Acids 3941 2. Carbopeptoids 3941 V. Single-Stranded Abiotic Foldamers 3944 A. Overview 3944 B. Backbones Utilizing Bipyridine Segments 3944 1. Pyridine−Pyrimidines 3944 2. Pyridine−Pyrimidines with Hydrazal Linkers 3945

Water as an Active Constituent in Cell Biology

Abstract: When Szent-Gyorgyi called water the “matrix of life”,1 he was echoing an old sentiment. Paracelsus in the 16th century said that “water was the matrix of the world and of all its creatures.”2 But Paracelsus’s notion of a matrixsan active substance imbued with fecund, life-giving propertiess was quite different from the picture that, until very recently, molecular biologists have tended to hold of water’s role in the chemistry of life. Although acknowledging that liquid water has some unusual and important physical and chemical propertiessits potency as a solvent, its ability to form hydrogen bonds, its amphoteric naturesbiologists have regarded it essentially as the backdrop on which life’s molecular components are arrayed. It used to be common practice, for example, to perform computer simulations of biomolecules in a vacuum. Partly this was because the computational intensity of simulating a polypeptide chain was challenging even without accounting for solvent molecules too, but it also reflected the prevailing notion that water does little more than temper or moderate the basic physicochemical interactions responsible for molecular biology. What Gerstein and Levitt said 9 years ago remains true today: “When scientists publish models of biological molecules in journals, they usually draw their models in bright colors and place them against a plain, black background”.3 Curiously, this neglect of water as an active component of the cell went hand in hand with the assumption that life could not exist without it. That was basically an empirical conclusion derived from our experience of life on Earth: environments without liquid water cannot sustain life, and special strategies are needed to cope with situations in which, because of extremes of either heat or cold, the liquid is scarce.4-6 The recent confirmation that there is at least one world rich in organic molecules on which rivers and perhaps shallow seas or bogs are filled with nonaqueous fluidsthe liquid hydrocarbons of Titan7smight now bring some focus, even urgency, to the question of whether water is indeed a * E-mail: p.ball@nature.com. Philip Ball is a science writer and a consultant editor for Nature, where he worked as an editor for physical sciences for more than 10 years. He holds a Ph.D. in physics from the University of Bristol, where he worked on the statistical mechanics of phase transitions in the liquid state. His book H2O: A Biography of Water (Weidenfeld & Nicolson, 1999) was a survey of the current state of knowledge about the behavior of water in situations ranging from planetary geomorphology to cell biology. He frequently writes about aspects of water science for both the popular and the technical media.

The design, synthesis, and evaluation of molecules that enable or enhance cellular uptake: Peptoid molecular transporters

Abstract: Certain proteins contain subunits that enable their active translocation across the plasma membrane into cells. In the specific case of HIV-1, this subunit is the basic domain Tat(49-57) (RKKRRQRRR). To establish the optimal structural requirements for this translocation process, and thereby to develop improved molecular transporters that could deliver agents into cells, a series of analogues of Tat(49-57) were prepared and their cellular uptake into Jurkat cells was determined by flow cytometry. All truncated and alanine-substituted analogues exhibited diminished cellular uptake, suggesting that the cationic residues of Tat(49-57) play a principal role in its uptake. Charge alone, however, is insufficient for transport as oligomers of several cationic amino acids (histidine, lysine, and ornithine) are less effective than Tat(49-57) in cellular uptake. In contrast, a 9-mer of l-arginine (R9) was 20-fold more efficient than Tat(49-57) at cellular uptake as determined by Michaelis-Menton kinetic analysis. The d-arginine oligomer (r9) exhibited an even greater uptake rate enhancement (>100-fold). Collectively, these studies suggest that the guanidinium groups of Tat(49-57) play a greater role in facilitating cellular uptake than either charge or backbone structure. Based on this analysis, we designed and synthesized a class of polyguanidine peptoid derivatives. Remarkably, the subset of peptoid analogues containing a six-methylene spacer between the guanidine head group and backbone (N-hxg), exhibited significantly enhanced cellular uptake compared to Tat(49-57) and even to r9. Overall, a transporter has been developed that is superior to Tat(49-57), protease resistant, and more readily and economically prepared.