Kou Okuro

Molecular adhesion based on multivalent interactions plays essential roles in various biological processes. Hence, "molecular glues" that can adhere to biomolecules may modulate biomolecular functions and therefore can be applied to therapeutics. This tutorial review describes design strategies for developing adhesive motifs for biomolecules based on multivalent interactions. We highlight a guanidinium ion-based salt-bridge as a key interaction for adhesion to biomolecules and discuss the applic

Dendron G1(Gu(+))(9)R and linear peptide oligomer Asn(TEG-Gu(+))(9), decorated with multiple guanidinium (Gu(+)) ions as sticky pendants via an oligo(oxyethylene) spacer, adhere to BSA and protein assemblies such as microtubules in aqueous buffers. Using fluorescently labeled G1(Gu(+))(9)R with pyrenyl and rhodamine focal cores, the adhesion process can be visualized by FRET or confocal laser scanning microscopy. The adhesion to microtubules leads to their stabilization against depolymerization

Water-soluble linear polymers GumBAn (m/n = 18/6, 12/12, and 6/18) with multiple guanidinium ion (Gu(+)) and boronic acid (BA) pendants in their side chains were synthesized as ATP-responsive modulators for enzyme activity. GumBAn polymers strongly bind to the phosphate ion (PO4(-)) and 1,2-diol units of ATP via the Gu(+) and BA pendants, respectively. As only the Gu(+) pendants can be used for proteins, GumBAn is able to modulate the activity of enzymes in response to ATP. As a proof-of-concept

Caspase-3 (Casp-3) is an enzyme that efficiently induces apoptosis, a form of programmed cell death. We report a dendritic molecular glue ^PCGlue that enables intracellular delivery of Casp-3 and its photoactivation. ^PCGlue carrying multiple guanidinium (Gu⁺) ion pendants via photocleavable linkages can tightly adhere to Casp-3 and deliver it into the cytoplasm mainly by direct penetration through the plasma membrane. Casp-3, whose surface is covered by <sup>PC</s

Transferrin (Tf) is known to induce transcytosis, which is a consecutive endocytosis/exocytosis event. We developed a Tf-appended nanocaplet (^TfNC⊃siRNA) for the purpose of realizing siRNA delivery into deep tissues and RNA interference (RNAi) subsequently. For obtaining ^TfNC⊃siRNA, a macromonomer (^AzGu) bearing multiple guanidinium (Gu⁺) ion units, azide (N₃) groups, and trityl (Trt)-protected thiol groups in the main chain, side chains, an

We developed a dendritic molecular glue ^PCGlue-NBD that can serve universally to "turn on" protein-protein interactions (PPIs) spatiotemporally. ^PCGlue-NBD carrying multiple guanidinium ion (Gu⁺) pendants can adhere strongly to target proteins and cover their surfaces including the PPI interface regions, thereby suppressing PPIs with their receptor proteins. Upon irradiation with UV light, ^PCGlue-NBD on a target protein is photocleaved at butyrate-subs

A sticky end: A heterotropic conjugate of actin and myosin–actomysin–is stabilized by a water-soluble dendritic “molecular glue” bearing nine pendant guanidinium ions (see picture; ATP= adenosine triphosphate, ADP=adenosine diphosphate). The ATP-driven sliding motion of actin filaments on a myosin-functionalized coverslip is decelerated or totally arrested with a higher-generation dendrimer, but not with a lower-generation one. Detailed facts of importance to specialist readers are published as

Water-soluble bioadhesive polymers bearing multiple guanidinium ion (Gu⁺) pendants at their side-chain termini (Glue _<i>n</i> -BA, <i>n</i> = 10 and 29) that were conjugated with benzamidine (BA) as a trypsin inhibitor were developed. The Glue _<i>n</i> -BA molecules are supposed to adhere to oxyanionic regions of the trypsin surface, even in buffer, <i>via</i> a multivalent Gu⁺/oxyanion salt-bridge interaction, such that their BA group properly blocks

PGlue(PZ), a pyrazoline (PZ)-based fluorescent adhesive which can be generated spatiotemporally in living systems, was developed. Since PGlue(PZ) carries many guanidinium ion (Gu(+)) pendants, it strongly adheres to various oxyanionic substrates through a multivalent salt-bridge interaction. PGlue(PZ) is given by bioorthogonal photopolymerization of a Gu(+)-appended monomer (Glue(TZ)), bearing tetrazole (TZ) and olefinic termini. Upon exposure to UV light, Glue(TZ) transforms into a nitrileimine

We developed a photoreactive molecular glue, ^BPGlue-N₃, which can provide a universal strategy to enhance the efficacy of DNA aptamers by temporary-to-permanent stepwise stabilization of their conjugates with target proteins. As a proof-of-concept study, we applied ^BPGlue-N₃ to the SL1 (DNA aptamer)/c-Met (target protein) conjugate system. ^BPGlue-N₃ can adhere to and temporarily stabilize this aptamer/protein conjugate multivalent

^FLNBD-BAM_PEG2k, bearing a nitrobenzoxadiazole (NBD) unit and an oleyl terminus conjugated via a poly(ethylene glycol) (PEG) spacer ( M_n = 2,000), was designed to fluorescently label cell membranes by docking its hydrophobic oleyl terminus. During laser scanning microscopy in a minimal essential medium (MEM), human hepatocellular carcinoma Hep3B cells labeled with ^FLNBD-BAM_PEG2k appeared to undergo optoporation at their plasma membrane. We co

High mechanical properties and rapid sol/gel phase transition are mutually exclusive in the hydrogels reported to date, most likely because the 3D crosslinked networks of mechanically robust hydrogels comprise bundled thick fibers that are not rapidly dissociable or formable. Herein, we report a visible light-responsive hydrogel that showed a rapid, reversible sol/gel phase transition despite its relatively high mechanical properties (storage modulus ~10³ Pa). To construct its 3D cros

We developed a dendritic molecular glue (GlueSS-BP) bearing multiple guanidinium ion (Gu+) pendants via a disulfide (SS) spacer as a carrier for intracellular siRNA delivery. GlueSS-BP adheres tigh...

Mechanoresponsive materials can harness mechanical forces to initiate molecular events and alter their physicochemical properties. Enzyme reactions, which enable diverse chemical transformations under mild conditions, have great potential as outputs of the mechanoresponse, especially in biological applications. Here, we present a hydrogel-based platform that realizes mechanotransduction to enzyme reactions through the modulation of multivalent salt-bridge interactions between a polymeric inhibit

Festgeklebt: Ein heterotropes Konjugat aus Actin und Myosin – Actomysin – wird durch einen wasserlöslichen „molekularen Klebstoff“, ein Dendrimer mit neun Guanidinium-Resten, stabilisiert (siehe Bild; ATP=Adenosintriphosphat, ADP=Adenosindiphosphat). Während das Dendrimer erster Generation die ATP-getriebene Gleitbewegung von Actinfilamenten auf dem Myosin-funktionalisierten Deckglas bremst oder zum Stillstand bringt, ist ein verwandtes Dendrimer nullter Generation dazu nicht in der Lage. Detail