MCY

Cambridge Healthtech Institute 第6届

Macrocyclics & Constrained Peptides

( 大环状胜肽和拘束胜肽 )

可穿透细胞的中分子药物

2018年4月4-5日 | | Hilton Bayfront | 加州圣地牙哥

 

有许多生物药物研究人员为了找出具有发展成为药品潜力的分子,而开始注意药物化学新领域的中分子。中分子药物代表了比小分子稍大的化合物,理论上能更有效参与较大标的(如蛋白质间交互作用或蛋白质/DNA复合体)之特定交互作用。另一方面中分子又比生物制剂及各种蛋白质药物来得小,不但可以穿透细胞抵达标的,也具有开发成口服药物的潜力。合成大环状胜肽和拘束胜肽是尺寸中等又易于溶解的环状结构,虽然满足了各方条件,但理论到现实之间仍有待努力。研究人员为了达成最佳设计,仍持续改良这个类别分子的「基准」与特性,维持此类分子的溶解度及细胞穿透能力是最主要的课题。本研讨会以大环状胜肽和拘束胜肽为主题,将介绍本领域的研究进展状况以及最新想法。


Final Agenda

Wednesday, April 4

12:30 pm Registration

12:45 Dessert Break in the Exhibit Hall with Poster Viewing

DESIGN RULES FOR MACROCYCLES

1:30 Welcome Remarks

Anjani Shah, PhD, Conference Director, Cambridge Healthtech Institute

1:35 Chairperson's Opening Remarks

Scott Lokey, PhD, Professor, Chemistry and Biochemistry, University of California, Santa Cruz

1:40 Lessons for the Design of Synthetic Macrocycles from Machine Learning

Adrian Whitty, PhD, Professor, Biochemistry, Boston University

2:10 Physical Chemical Properties for Drug Design in Beyond Rule of Five Chemical Space

Marina Shalaeva, PhD, Principal Scientist, Medicinal Design, Pfizer

New concepts and methods are being developed for evaluation and modulation of properties of Bro5 compounds to achieve acceptable PK/PD in drug candidate. In particular, the PLRP-S method for estimating lipophilicity and ionization in nonpolar membrane-like environment is described. A fast chromatographic assay is used to asses lipophilicity-ionization patterns of lipophilic, low solubility Bro5 compounds in combination with pKa by MCE, while EPSA and ElogD are used to drive passive permeability and drug efficiency (lipE).

2:40 Lipophilic Permeability Efficiency (LPE) Enables the Identification and Quantification of Structural Effects on Macrocycle Permeability

Matthew R. Naylor, PhD, LIFA Postdoctoral Fellow, Eli Lilly & Co.

Macrocycle scaffold structure determines the balance between lipophilicity and aqueous solubility in the pursuit of bRo5 therapeutics capable of passive cell permeability. Current techniques to identify such structure are time-intensive (NMR analysis) or challenging on large peptides (in silico prediction). Combining a simple hydrocarbon lipophilicity measurement with a predictor of aqueous solubility, Lipophilic Permeability Efficiency (LPE) quantifies the intrinsic ability of diverse bRo5 scaffolds to hide backbone or sidechain polarity for cell permeability.

3:10 Conformational Sampling of Macrocycles in Solution

Paul Hawkins, PhD, Head, Scientific Solutions, OpenEye Scientific Software

Some types of macrocyclic molecules have been shown to be orally bioavailable ligands for targets such as GPCRs and protein-protein interfaces, which requires then to be able to permeate cell membranes effectively. The means by which high molecular weight macrocycles are able to be membrane permeable has been the subject of some recent study, but no clear conclusions have yet been reached. In this presentation we discuss how to model effectively the conformational properties of macrocycles in different environments and how experimental data gathered in solution, particularly from NMR, can be used to improve that sampling.

3:40 Refreshment Break in the Exhibit Hall with Poster Viewing

4:30 Property-Based Drug Design beyond Ro5 - Lessons Learned from AbbVie's Drugs and Compound Collection

Phil Cox, PhD, Senior Principal Scientist, Chemistry Group Leader, Discovery Chemistry and Technology, AbbVie, Inc.

This presentation will focus on the lessons learned from an initiative to analyze AbbVie's internal database of compounds beyond Ro5 (including macrocycles).

5:00 Rationalizing the Passive Membrane Permeability of Cyclic Peptides

Sereina Riniker, PhD, Assistant Professor, Laboratory of Physical Chemistry, ETH Zurich

The hypothesis for the passive membrane permeability of cyclic peptides involves the interconversion between "open" conformations and "closed" conformations prior to the entering of the membrane. Using kinetic models based on molecular dynamics (MD) simulations in polar and apolar environments, a rationale for the "permeability cliff" presented by the natural product cyclosporine A and its synthetic derivative cyclosporine E as well as for a recently published series of cyclic decapeptides is provided.

5:30 Breakout Discussions

6:15 End of Day

6:30 Dinner Short Courses*

*Separate registration required

Thursday, April 5

8:00 am Breakfast Presentation: Improvements in NMR Approaches to Fragment Based Screening

Donna Baldisseri, Senior Applications Scientist, Bruker BioSpin

FBDD is a powerful search engine for identification of fragments that bind to disease relevant target proteins ultimately leading to drug candidates. NMR-based FBDD screening requires compound library validation, preparation of hundreds of samples per campaign, automated acquisition, processing of thousands of spectra, and their analysis for binding assessment. Here is described the streamlined solutions offered by Bruker, automating this pipeline to improve the speed and productiveness of FBDD screening for the pharmaceutical industry.

8:45 Plenary Session Welcome Remarks from Event Director

Anjani Shah, PhD, Conference Director, Cambridge Healthtech Institute

8:50 Sponsored Plenary Keynote Introduction (Opportunity Available)


8:55 PLENARY KEYNOTE: Activity-Based Proteomics: Protein and Ligand Discovery on a Global Scale

Benjamin F. Cravatt, PhD, Professor and Co-Chair, Department of Molecular Medicine, The Scripps Research Institute

To address uncharacterized proteins, we have introduced chemical proteomic technologies that globally profile the functional state of proteins in native biological systems. Among these methods is activity-based protein profiling (ABPP), which utilizes chemical probes to map activity states of large numbers of proteins in parallel. I will discuss the application of ABPP to discover and functionally annotate proteins in mammalian physiology and disease, and the generation and implementation of advanced ABPP platforms for proteome-wide ligand discovery.

9:45 Coffee Break in the Exhibit Hall with Poster Viewing

BEYOND NATURAL PEPTIDES AND AMINO ACIDS

10:40 Chairperson's Remarks

Maxwell D. Cummings, PhD, Senior Principal Scientist, Computational Chemistry, Discovery Sciences, Janssen R&D


10:45 FEATURED PRESENTATION: The RaPID Discovery of Bioactive Pseudo-Natural Peptides

Hiroaki Suga, PhD, Professor, Department of Chemistry, School of Science, The University of Tokyo

This lecture will describe the most recent development in the genetic code reprogramming technology that enables us to express pseudo-natural peptides. The technology involves (1) efficient macrocyclization of peptides, (2) incorporation of non-standard amino acids, such as N-methyl amino acids, (3) reliable synthesis of libraries with the complexity of more than a trillion members, (4) rapid discovery of potent bioactive pseudo-natural peptides by the RaPID system (or PDPS).

11:15 Lead Optimization of Natural-Product Derived NaV1.7 Inhibitory Disulfide-Rich Peptides

Kaustav Biswas, PhD, Principal Scientist, Hybrid Modality Engineering, Amgen, Inc.

My talk details Amgen's program directed at inhibition of the voltage-gated sodium channel NaV1.7 for pain and itch using hits from a venom screen. We identified novel toxin peptides from tarantula venom which have disulfide-rich folded motifs. Using a combination of positional scanning and peptide-ion channel molecular docking studies, we will discuss the discovery of synthetic analogues with activity in ex vivo and in vivo behavioral NaV1.7-dependent models. 

11:45 Sponsored Presentation (Opportunity Available)

12:00 pm Discovery of Potent and Orally Bioavailable Macrocyclic Peptide-Peptoid Hybrid CXCR7 Modulators

Elnaz Menhaji-Klotz, PhD, Senior Principal Scientist, Internal Medicine Chemistry, Pfizer

While several small molecules have been identified that modulate the activity of CXCR7, an attractive drug target for a variety of disease indications, peptidic macrocycles may provide additional advantages in terms of potency, selectivity, and reduced off-target activity. We report on a series of peptidic macrocycles that bind to CXCR7 and also incorporate an N-linked peptoid functionality in order to overcome the poor permeability associated with peptides. The peptoid group also enabled us to explore side chain diversity well beyond that of natural amino acids.

Schrodinger 12:30 Luncheon Presentation to be Announced

1:30 Dessert Break in the Exhibit Hall with Poster Awards

CYCLIC PEPTIDES: DRUG DEVELOPMENT CHALLENGES

2:15 Chairperson's Remarks

Adrian Whitty, PhD, Professor, Biochemistry, Boston University

2:20 Cell Penetration Profiling for Biotherapeutics

Joshua Kritzer, PhD, Associate Professor, Chemistry, Tufts University

Several classes of biomolecules have emerged as exciting potential therapies, but their development has been impeded by imprecise measurements of intracellular delivery. The Kritzer lab has devised a new method for quantitating cell penetration, the ChloroAlkane Penetration Assay (CAPA). CAPA is inexpensive and high-throughput, and it can quantitate penetration to individual cellular compartments. We are using CAPA to comprehensively profile cell penetration for diverse biomolecules and drug delivery systems.

2:50 Achieving Passive Permeability and Oral Bioavailability in Synthetic Cyclic Peptides

Scott Lokey, PhD, Professor, Chemistry and Biochemistry, University of California, Santa Cruz

3:20 Polar Hinges as Functionalized Conformational Constraints in (Bi)Cyclic Peptides

Robert Liskamp, PhD, Chair of Chemical Biology and Medicinal Chemistry, Chemistry, University of Glasgow

We wish to devise (cyclic) peptides and peptidomimetics as protein-protein interactions (PPI) inhibitors. Polar hinges have been developed for cyclization of peptides leading to bicyclic peptides and cyclized peptides with improved solubility and biological activity. Increasingly, we note that a good aqueous solubility of peptides is an absolute prerequisite not only to be able to handle and purify our target peptides but it is also crucial for biological activity characterization.

3:50 Refreshment Break

4:20 Cyclotide Antagonists of the HDM2-HDMX RING-Mediated E3 Ligase

Julio Camarero, PhD, Professor, Pharmacology and Pharmaceutical Sciences, University of Southern California

The cyclotide scaffold has a tremendous potential for the development of therapeutic leads based on their extraordinary stability and potential for grafting applications. We will show an example, where a large cyclotide-based genetically encoded library was used to screen for low nanomolar antagonists for the Hdm2-HdmX RING-mediated E3 ligase activity. We will also present different strategies to improve the cellular uptake and pharmacokinetic profiles of bioactive cyclotides.

4:50 Constrained Oligomers Targeting the Ubiquitin-Proteasome Pathway

Thomas Kodadek, PhD, Professor of Chemistry; Associate Dean of Graduate and Post-Doctoral Studies, The Scripps Research Institute

5:20 Novel, Simple and Effective Helix Stabilizing Strategies Lead to Potent and Selective Bcl-2 Antagonists

Maurizio Pellecchia, PhD, Professor of Biomedical Sciences, University of California, Riverside (UCR) School of Medicine

Members of the anti-apoptotic Bcl-2 proteins, including Bcl-2, Mcl-1, Bcl-xL, and Bfl-1, inhibit apoptosis by selectively binding to conserved a-helical regions, named BH3 domains, of pro-apoptotic proteins such as Bim, Bid, or NOXA. Most advanced attempts to obtain pharmacologically active BH3 peptides rely on "hydrocarbon stapling" to constrain alpha-helical peptides generally of > 20 aminoacids in length. However, these have not yet resulted in viable clinical candidates. Here, I will report on a novel, simple, general and effective strategy to obtain alpha-helical short peptides (13-17 aa) that potently and specifically target Bfl-1, Bcl-xL, and Mcl-1.

5:50 End of Conference

* 活动内容有可能不事先告知作更动及调整。