Leland Stanford Junior University

Cellgate, Inc.

Kai Pharmaceuticals, Inc.

International Business Machines Corporation

University of California

Paul A Wender

Jonathan B Rothbard

Lalitha V S Sista

Thorsten A Kirschberg

P Leo McGrane

Robert M Waymouth

Stephen Ho

Ryan Quiroz

Akira Shimizu

Steven Ryckbosch

Matthew C Stevens

Clayton Hardman

Matthew S Jeffreys

Jack Leider Sloane

Hongjie Dai

Cheol-Min Park

Ronald Levy

Zhuang Liu

Nadine Wong Shi Kam

Blaise Lippa

Colin J McKinlay

Christina Barnes Cooley

Brian Trantow

Jung-Min Kee

Christopher L VanDeusen

Kevin W Hinkle

Kanaka Pattabiraman

Erin T Pelkey

Theodore C Jessop

Xiaoyu Zang

Tim R Blake

Ole Audun Werner Haabeth

Adrienne Sallets

James L Hedrick

Adam James Schrier

Orion D Jankowski

Fredrik Nederberg

Lars V Heumann

Erik Kreider

Bahram A Parvin

Elizabeth J Mieuli

Lee Robert Wright

Lynette Cegelski

Joel M Hyman

Nancy Lynn Benner

Katherine N Keenan

Alexandra Antonoplis

Jack Sloane

Leo P McGrane

Erika Geihe Stanzl

Elena A Goun

Erika Geihe

Lisa R Jones

Jeffrey M Warrington

Jeffrey Warrington

Matthew Kiesewetter

Marc J Scanio

Rainer Kramer

Elie A Tabet

Carolyn Gauntlett

Dennis Fournogerakis

Melanie Huttner

Pierre-Luc Boudreault

Rebecca Mcclellan

Brian DeChristopher

Matthew Frank

Jessica R Vargas

Katherine Near

Nancy Benner

Colin Mckinlay

Methods for preparing a variety of bryostatin compounds are provided. The subject methods provide for preparation of bryostatin 1 in multi-gram quantities in a low and unprecedented number of convergent synthetic steps from commercially available materials. The subject methods are scalable with low estimated material costs and can provide enough material to meet clinical needs. Also provided are a variety of bryostatin analog compounds, and prodrug forms thereof, which are synthetically accessible via the subject methods and pharmaceutical compositions including the same.

Bryostatin compounds and methods of preparing the same

There are provided herein, inter alia, complexes, compositions and methods for the delivery of nucleic acid into a cell in vivo. The complexes, compositions and methods may facilitate complexation, protection, delivery and release of oligonucleotides and polyanionic cargos into target cells, tissues, and organs both in vitro and in vivo.

Hybrid immolative cell-penetrating complexes for nucleic acid delivery

Antibiotic agents conjugated to a guanidinium-rich molecular transporter (GR-MoTr) are provided. The drug conjugates show surprising increases in efficacy compared to the unconjugated drug in difficult-to-treat bacterial infections including biofilms, stationary and persister cells, and multi-drug resistant bacteria, as well as intracellular bacteria.

Composition and method for new antimicrobial agents with secondary mode of action provided by conjugation of an antimicrobial to a guanidinium-rich molecular transporter

There are provided herein, inter alia, cationic amphipathic polymers, complexes, and compositions comprising same, and methods for their use including for the delivery of therapeutic, diagnostic and imaging agents, including nucleic acids, into a cell. The complexes, compositions and methods may facilitate delivery and targeted release of the therapeutic, diagnostic and imaging agents to particular cell types and tissues.

Immolative cell-penetrating complexes for nucleic acid delivery to the lung

Embodiments of prodrugs of PKC modulators that show efficacy coupled with low levels of toxicity and improved stability are provided. The prodrug compounds are useful in academic research (animal studies), as candidates for preclinical research, and as therapeutic agents. By taking advantage of a pharmacophore-based strategy, this design strategy provides access to prodrugs of PKC modulators of diverse scaffolds including tigliane diterpenes, ingenane diterpenes, daphnane diterpene orthoesters, diacylglycerols, and bryostatins, and analogs thereof. In particular, embodiments of the prodrug ingenane esters having substitutions at C20 and their use as therapeutic agents are provided.

Prodrug derivatives of protein kinase C modulators

Guanidinium-rich oligophosphotriesters transporter compounds and methods of making and using the same are provided. Also provided are pharmaceutical compositions that include the subject transporter compounds, where the transporter can be joined to a cargo of interest, and is formulated with a pharmaceutically acceptable excipient. Formulations may be provided in a unit dose, where the dose provides an amount of the compound effective to afford a desired therapeutic effect. Methods of using the subject transporter compounds to deliver a cargo moiety to a cell are provided, where the method can include contacting a target cell with the transporter compound. The subject methods can be performed in vitro or in vivo.

Cell-penetrating, guanidinium-rich oligophosphotriesters for drug and probe delivery

Co-oligomer compounds, complexes of the same with polyanions, such as siRNAs, and methods for using the same are provided. the delivery of polynucleotides, into a cell. The subject co-oligomers include at least a liphopilic monomer and at least a hydrophilic monomer (e.g., a guanidinium containing monomer). In some embodiments, the co-oligomer compounds are capable of complexing a siRNA of interest, thereby increasing the cell permeability of the siRNA, prior to release of the siRNA into the cell. In some embodiments, the subject method is a method of delivery a siRNA into a cell. In some embodiments, the subject method is a method of reducing expression of a protein target of a siRNA of interest. The subject co-oligomer/siRNA complexes may be formulated and administered to a subject to treat a condition resulting from expression of a protein target of the siRNA of interest.

Amphipathic co-oligomers for the delivery of siRNA

The introduction of tools to study, control or expand the inner-workings of algae has been slow to develop. Provided are embodiments of a molecular method based on guanidinium-rich molecular transporters (GR-MoTrs) for bringing molecular cargos into algal cells. The methods of the disclosure have been shown to work in wild-type algae that have an intact cell wall. Developed using, this method is also successful with less studied algae, includingand, thus providing a new and versatile tool for algal research and modification. The method of delivering a cargo compound to an algal cell comprises contacting an algal cell with a guanidinium-rich delivery vehicle comprising a guanidinium-rich molecular transporter (GR-MoTr) linked to a cargo compound desired to be delivered to the algal cell, whereby the guanidinium-rich molecular transporter can traverse the algal cell wall, thereby delivering the cargo compound to the algal cell.

Method for delivery of small molecules and proteins across the cell wall of algae using molecular transporters

Embodiments of the present disclosure provide for prostratin analogs, bryostatin analogs, prodrugs of prostratin and prostratin analogs, methods of making prostratin analogs, and methods of making prodrugs of prostratin and prostratin analogs, methods of use of prostratin analogs, bryostatin analogs, and prodrugs thereof, and the like.

Prostratin analogs, bryostatin analogs, prodrugs, synthetic methods, and methods of use

Methods and materials for delivering biologically active molecules to cells in vitro or in vivo are provided. The methods and materials use carbon nanotubes or other hydrophobic particles, tubes and wires, functionalized with a linking group that is covalently bound to the nanotubes, or, alternatively, to the biologically active molecule, such as a protein. The biologically active molecule is preferably released from the nanotube when the complex has been taken up in an endosome.

Hydrophobic nanotubes and nanoparticles as transporters for the delivery of drugs into cells

Biologically active compounds related to the bryostatin family of compounds, having simplified spacer domains and/or improved recognition domains are disclosed, including methods of preparing and utilizing the same.

Bryostatin analogues, synthetic methods and uses

This invention provides compositions and methods for enhancing delivery of drugs and other agents across epithelial tissues, including into and across ocular tissues and the like. The compositions and methods are also useful for delivery across endothelial tissues, including the blood brain barrier. The compositions and methods employ a delivery enhancing transporter that has sufficient guanidino or amidino sidechain moieties to enhance delivery of a compound conjugated to the reagent across one or more layers of the tissue, compared to the non-conjugated compound. The delivery-enhancing polymers include, for example, poly-arginine molecules that are preferably between about 6 and 25 residues in length.

Compositions and methods for enhancing drug delivery across and into ocular tissues

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Menlo Park, CA, United States of America

Paul A Wender