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Surface-Matrix Screening Identifies Semi-specific Interactions that Improve Potency of a Near Pan-reactive HIV-1-Neutralizing Antibody.
Kwon YD, Chuang GY, Zhang B, Bailer RT, Doria-Rose NA, Gindin TS, Lin B, Louder MK, McKee K, O'Dell S, Pegu A, Schmidt SD, Asokan M, Chen X, Choe M, Georgiev IS, Jin V, Pancera M, Rawi R, Wang K, Chaudhuri R, Kueltzo LA, Manceva SD, Todd JP, Scorpio DG, Kim M, Reinherz EL, Wagh K, Korber BM, Connors M, Shapiro L, Mascola JR, Kwong PD
(2018) Cell Rep 22: 1798-1809
MeSH Terms: Antibodies, Neutralizing, Cell Membrane, HIV Antibodies, HIV Envelope Protein gp41, HIV-1, Half-Life, Humans, Neutralization Tests, Polysaccharides, Protein Binding
Show Abstract · Added March 14, 2018
Highly effective HIV-1-neutralizing antibodies could have utility in the prevention or treatment of HIV-1 infection. To improve the potency of 10E8, an antibody capable of near pan-HIV-1 neutralization, we engineered 10E8-surface mutants and screened for improved neutralization. Variants with the largest functional enhancements involved the addition of hydrophobic or positively charged residues, which were positioned to interact with viral membrane lipids or viral glycan-sialic acids, respectively. In both cases, the site of improvement was spatially separated from the region of antibody mediating molecular contact with the protein component of the antigen, thereby improving peripheral semi-specific interactions while maintaining unmodified dominant contacts responsible for broad recognition. The optimized 10E8 antibody, with mutations to phenylalanine and arginine, retained the extraordinary breadth of 10E8 but with ∼10-fold increased potency. We propose surface-matrix screening as a general method to improve antibodies, with improved semi-specific interactions between antibody and antigen enabling increased potency without compromising breadth.
Published by Elsevier Inc.
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10 MeSH Terms
Optimization of the choline transporter (CHT) inhibitor ML352: Development of VU6001221, an improved in vivo tool compound.
Bertron JL, Ennis EA, Tarr CJ, Wright J, Dickerson JW, Locuson CW, Blobaum AL, Rook JM, Blakely RD, Lindsley CW
(2016) Bioorg Med Chem Lett 26: 4637-4640
MeSH Terms: Animals, Benzamides, Dose-Response Relationship, Drug, Half-Life, Inhibitory Concentration 50, Isoxazoles, Membrane Transport Proteins, Oxazoles, Piperidines, Rats, Structure-Activity Relationship
Show Abstract · Added March 21, 2018
This Letter describes the further lead optimization of the CHT inhibitor probe, ML352 (VU0476201), and the development of VU6001221, an improved in vivo tool. A multi-dimensional optimization effort encountered steep SAR, and ultimately, subtle tuning of the electronics of the central phenyl core provided VU6001221, a CHT inhibitor with comparable potency for choline uptake inhibition as ML352, yet improved PK and CNS penetration. Moreover, VU6001221 enabled evaluation, for the first time, of a CHT inhibitor in a standard preclinical rodent cognition model, novel object recognition (NOR). We observed VU6001221 to elicit a dose-responsive increase in NOR, raising the possibility of agonism of synaptic α7 nicotinic ACh receptors by elevated extracellular choline, that if confirmed would represent a novel molecular strategy to enhance cognition.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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11 MeSH Terms
Optimization of the Solubility of HIV-1-Neutralizing Antibody 10E8 through Somatic Variation and Structure-Based Design.
Kwon YD, Georgiev IS, Ofek G, Zhang B, Asokan M, Bailer RT, Bao A, Caruso W, Chen X, Choe M, Druz A, Ko SY, Louder MK, McKee K, O'Dell S, Pegu A, Rudicell RS, Shi W, Wang K, Yang Y, Alger M, Bender MF, Carlton K, Cooper JW, Blinn J, Eudailey J, Lloyd K, Parks R, Alam SM, Haynes BF, Padte NN, Yu J, Ho DD, Huang J, Connors M, Schwartz RM, Mascola JR, Kwong PD
(2016) J Virol 90: 5899-5914
MeSH Terms: Animals, Antibodies, Neutralizing, Chemistry Techniques, Analytical, Crystallography, X-Ray, Disulfides, HIV Antibodies, HIV-1, Half-Life, High-Throughput Nucleotide Sequencing, Humans, Hydrophobic and Hydrophilic Interactions, Macaca mulatta, Models, Molecular, Solubility
Show Abstract · Added May 3, 2017
UNLABELLED - Extraordinary antibodies capable of near pan-neutralization of HIV-1 have been identified. One of the broadest is antibody 10E8, which recognizes the membrane-proximal external region (MPER) of the HIV-1 envelope and neutralizes >95% of circulating HIV-1 strains. If delivered passively, 10E8 might serve to prevent or treat HIV-1 infection. Antibody 10E8, however, is markedly less soluble than other antibodies. Here, we describe the use of both structural biology and somatic variation to develop optimized versions of 10E8 with increased solubility. From the structure of 10E8, we identified a prominent hydrophobic patch; reversion of four hydrophobic residues in this patch to their hydrophilic germ line counterparts resulted in an ∼10-fold decrease in turbidity. We also used somatic variants of 10E8, identified previously by next-generation sequencing, to optimize heavy and light chains; this process yielded several improved variants. Of these, variant 10E8v4 with 26 changes versus the parent 10E8 was the most soluble, with a paratope we showed crystallographically to be virtually identical to that of 10E8, a potency on a panel of 200 HIV-1 isolates also similar to that of 10E8, and a half-life in rhesus macaques of ∼10 days. An anomaly in 10E8v4 size exclusion chromatography that appeared to be related to conformational isomerization was resolved by engineering an interchain disulfide. Thus, by combining a structure-based approach with natural variation in potency and solubility from the 10E8 lineage, we successfully created variants of 10E8 which retained the potency and extraordinary neutralization breadth of the parent 10E8 but with substantially increased solubility.
IMPORTANCE - Antibody 10E8 could be used to prevent HIV-1 infection, if manufactured and delivered economically. It suffers, however, from issues of solubility, which impede manufacturing. We hypothesized that the physical characteristic of 10E8 could be improved through rational design, without compromising breadth and potency. We used structural biology to identify hydrophobic patches on 10E8, which did not appear to be involved in 10E8 function. Reversion of hydrophobic residues in these patches to their hydrophilic germ line counterparts increased solubility. Next, clues from somatic variants of 10E8, identified by next-generation sequencing, were incorporated. A combination of structure-based design and somatic variant optimization led to 10E8v4, with substantially improved solubility and similar potency compared to the parent 10E8. The cocrystal structure of antibody 10E8v4 with its HIV-1 epitope was highly similar to that with the parent 10E8, despite 26 alterations in sequence and substantially improved solubility. Antibody 10E8v4 may be suitable for manufacturing.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
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Lead optimization of the VU0486321 series of mGlu(1) PAMs. Part 2: SAR of alternative 3-methyl heterocycles and progress towards an in vivo tool.
Garcia-Barrantes PM, Cho HP, Metts AM, Blobaum AL, Niswender CM, Conn PJ, Lindsley CW
(2016) Bioorg Med Chem Lett 26: 751-756
MeSH Terms: Allosteric Regulation, Animals, Antipsychotic Agents, Coumarins, Furans, Half-Life, Heterocyclic Compounds, Humans, Protein Binding, Rats, Receptors, Metabotropic Glutamate, Schizophrenia, Structure-Activity Relationship
Show Abstract · Added February 18, 2016
This Letter describes the further lead optimization of the VU0486321 series of mGlu1 positive allosteric modulators (PAMs), driven by recent genetic data linking loss of function GRM1 to schizophrenia. Steep and caveat-laden SAR plagues the series, but ultimately potent mGlu1 PAMs (EC50s ∼5 nM) have resulted with good DMPK properties (low intrinsic clearance, clean CYP profile, modest Fu) and CNS penetration (Kps 0.25-0.97), along with up to >450-fold selectivity versus mGlu4 and mGlu5.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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13 MeSH Terms
Development of Novel, CNS Penetrant Positive Allosteric Modulators for the Metabotropic Glutamate Receptor Subtype 1 (mGlu1), Based on an N-(3-Chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide Scaffold, That Potentiate Wild Type and Mutant mGlu1 Receptors Found in Schizophrenics.
Garcia-Barrantes PM, Cho HP, Niswender CM, Byers FW, Locuson CW, Blobaum AL, Xiang Z, Rook JM, Conn PJ, Lindsley CW
(2015) J Med Chem 58: 7959-71
MeSH Terms: Animals, Central Nervous System, Epilepsy, GABA Agonists, GABA Modulators, Half-Life, Humans, Molecular Conformation, Rats, Receptor, Metabotropic Glutamate 5, Receptors, Metabotropic Glutamate, Schizophrenia, Structure-Activity Relationship
Show Abstract · Added February 18, 2016
The therapeutic potential of selective mGlu1 activation is vastly unexplored relative to the other group I mGlu receptor, mGlu5; therefore, our lab has focused considerable effort toward developing mGlu1 positive allosteric modulators (PAMs) suitable as in vivo proof of concept tool compounds. Optimization of a series of mGlu1 PAMs based on an N-(3-chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide scaffold provided 17e, a potent (mGlu1 EC50 = 31.8 nM) and highly CNS penetrant (brain to plasma ratio (Kp) of 1.02) mGlu1 PAM tool compound, that potentiated not only wild-type human mGlu1 but also mutant mGlu1 receptors derived from deleterious GRM1 mutations found in schizophrenic patients. Moreover, both electrophysiological and in vivo studies indicate the mGlu1 ago-PAMs/PAMs do not possess the same epileptiform adverse effect liability as mGlu5 ago-PAMs/PAMs and maintain temporal activity suggesting a broader therapeutic window.
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Synthesis and structure-activity relationships of a series of 4-methoxy-3-(piperidin-4-yl)oxy benzamides as novel inhibitors of the presynaptic choline transporter.
Bollinger SR, Engers DW, Ennis EA, Wright J, Locuson CW, Lindsley CW, Blakely RD, Hopkins CR
(2015) Bioorg Med Chem Lett 25: 1757-1760
MeSH Terms: Animals, Benzamides, HEK293 Cells, Half-Life, Humans, Membrane Transport Proteins, Piperidines, Protein Binding, Rats, Structure-Activity Relationship, Symporters, Tissue Distribution
Show Abstract · Added September 28, 2015
The synthesis and SAR of 4-methoxy-3-(piperidin-4-yl) benzamides identified after a high-throughput screen of the MLPCN library is reported. SAR was explored around the 3-piperidine substituent as well as the amide functionality of the reported compounds. Starting from the initial lead compounds, 1-7, iterative medicinal chemistry efforts led to the identification of ML352 (10m). ML352 represents a potent and selective inhibitor of CHT based on a drug-like scaffold.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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12 MeSH Terms
Discovery and SAR of novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5).
Martín-Martín ML, Bartolomé-Nebreda JM, Conde-Ceide S, Alonso de Diego SA, López S, Martínez-Viturro CM, Tong HM, Lavreysen H, Macdonald GJ, Steckler T, Mackie C, Bridges TM, Daniels JS, Niswender CM, Noetzel MJ, Jones CK, Conn PJ, Lindsley CW, Stauffer SR
(2015) Bioorg Med Chem Lett 25: 1310-7
MeSH Terms: Allosteric Regulation, Animals, Antipsychotic Agents, Brain, Drug Evaluation, Preclinical, Half-Life, Heterocyclic Compounds, 2-Ring, Humans, Imidazoles, Locomotion, Microsomes, Liver, Protein Binding, Pyrimidinones, Rats, Receptor, Metabotropic Glutamate 5, Structure-Activity Relationship
Show Abstract · Added February 19, 2015
We report the discovery and SAR of two novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of several structural features in the western and eastern part of the imidazopyrimidinone core and combinations thereof, revealed compound 4a as a mGlu5 PAM with good in vitro potency and efficacy, acceptable drug metabolism and pharmacokinetic (DMPK) properties and in vivo efficacy in an amphetamine-based model of psychosis. However, the presence of CNS-mediated adverse effects in preclinical species precluded any further in vivo evaluation.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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Further optimization of the M5 NAM MLPCN probe ML375: tactics and challenges.
Kurata H, Gentry PR, Kokubo M, Cho HP, Bridges TM, Niswender CM, Byers FW, Wood MR, Daniels JS, Conn PJ, Lindsley CW
(2015) Bioorg Med Chem Lett 25: 690-4
MeSH Terms: Allosteric Regulation, Animals, Brain, Half-Life, Humans, Imidazoles, Indoles, Microsomes, Liver, Protein Binding, Rats, Receptor, Muscarinic M5, Structure-Activity Relationship
Show Abstract · Added February 19, 2015
This Letter describes the continued optimization of the MLPCN probe ML375, a highly selective M5 negative allosteric modulator (NAM), through a combination of matrix libraries and iterative parallel synthesis. True to certain allosteric ligands, SAR was shallow, and the matrix library approach highlighted the challenges with M5 NAM SAR within in this chemotype. Once again, enantiospecific activity was noted, and potency at rat and human M5 were improved over ML375, along with slight enhancement in physiochemical properties, certain in vitro DMPK parameters and CNS distribution. Attempts to further enhance pharmacokinetics with deuterium incorporation afforded mixed results, but pretreatment with a pan-P450 inhibitor (1-aminobenzotriazole; ABT) provided increased plasma exposure.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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Upstream open reading frame in 5'-untranslated region reduces titin mRNA translational efficiency.
Cadar AG, Zhong L, Lin A, Valenzuela MO, Lim CC
(2014) Biochem Biophys Res Commun 453: 185-91
MeSH Terms: 5' Untranslated Regions, Animals, Base Sequence, Cell Line, Connectin, Doxorubicin, Gene Expression Regulation, HEK293 Cells, Half-Life, Humans, Mice, Molecular Sequence Data, Myocytes, Cardiac, Open Reading Frames, Polymorphism, Single Nucleotide, Protein Kinases, RNA Stability, RNA, Messenger, Rats, Sarcomeres, Sequence Homology, Nucleic Acid
Show Abstract · Added February 19, 2015
Titin is the largest known protein and a critical determinant of myofibril elasticity and sarcomere structure in striated muscle. Accumulating evidence that mRNA transcripts are post-transcriptionally regulated by specific motifs located in the flanking untranslated regions (UTRs) led us to consider the role of titin 5'-UTR in regulating its translational efficiency. Titin 5'-UTR is highly homologous between human, mouse, and rat, and sequence analysis revealed the presence of a stem-loop and two upstream AUG codons (uAUGs) converging on a shared in frame stop codon. We generated a mouse titin 5'-UTR luciferase reporter construct and targeted the stem-loop and each uAUG for mutation. The wild-type and mutated constructs were transfected into the cardiac HL-1 cell line and primary neonatal rat ventricular myocytes (NRVM). SV40 driven 5'-UTR luciferase activity was significantly suppressed by wild-type titin 5'-UTR (∼ 70% in HL-1 cells and ∼ 60% in NRVM). Mutating both uAUGs was found to alleviate titin 5'-UTR suppression, while eliminating the stem-loop had no effect. Treatment with various growth stimuli: pacing, PMA or neuregulin had no effect on titin 5'-UTR luciferase activity. Doxorubicin stress stimuli reduced titin 5'-UTR suppression, while H2O2 had no effect. A reported single nucleotide polymorphism (SNP) rs13422986 at position -4 of the uAUG2 was introduced and found to further repress titin 5'-UTR luciferase activity. We conclude that the uAUG motifs in titin 5'-UTR serve as translational repressors in the control of titin gene expression, and that mutations/SNPs of the uAUGs or doxorubicin stress could alter titin translational efficiency.
Copyright © 2014 Elsevier Inc. All rights reserved.
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21 MeSH Terms
Position and length of fatty acids strongly affect receptor selectivity pattern of human pancreatic polypeptide analogues.
Mäde V, Bellmann-Sickert K, Kaiser A, Meiler J, Beck-Sickinger AG
(2014) ChemMedChem 9: 2463-74
MeSH Terms: Amino Acid Sequence, Animals, Anti-Obesity Agents, COS Cells, Cercopithecus aethiops, Fatty Acids, Half-Life, Humans, Kinetics, Ligands, Liver, Molecular Sequence Data, Pancreatic Polypeptide, Receptors, Neuropeptide Y
Show Abstract · Added January 24, 2015
Pancreatic polypeptide (PP) is a satiety-inducing gut hormone targeting predominantly the Y4 receptor within the neuropeptide Y multiligand/multireceptor family. Palmitoylated PP-based ligands have already been reported to exert prolonged satiety-inducing effects in animal models. Here, we suggest that other lipidation sites and different fatty acid chain lengths may affect receptor selectivity and metabolic stability. Activity tests revealed significantly enhanced potency of long fatty acid conjugates on all four Y receptors with a preference of position 22 over 30 at Y1 , Y2 and Y5 receptors. Improved Y receptor selectivity was observed for two short fatty acid analogues. Moreover, [K(30)(E-Prop)]hPP2-36 (15) displayed enhanced stability in blood plasma and liver homogenates. Thus, short chain lipidation of hPP at key residue 30 is a promising approach for anti-obesity therapy because of maintained selectivity and a sixfold increased plasma half-life.
© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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