Generalizing the Concept of Specific Compound Formulation Additives towards Non‐Fluorescent Drugs: A Solubilization Study on Potential Anti‐Alzheimer‐Active Small‐Molecule Compounds

Abstract

Tailor-made compound formulation additives enable the testing of potential drugs with undesirable pharmacological profiles. A combinatorial approach using Raman microscopy as the readout method is presented to select peptide sequences from large one-bead-one-compound libraries. The resulting peptide-PEG conjugates solubilize potential prophylactic and therapeutic anti-Alzheimer compounds and can be used as specific additives not only for fluorescent but also for non-fluorescent compounds.

Gaining Insights into Specific Drug Formulation Additives for Solubilizing a Potential Anti‐Alzheimer Disease Drug B4A1

“…Where the capacity drop for replacements of Phe1 and Lys7 reached about 43%–45% (0.43–0.45 × 10 −3 m B4A1/carrier, a Phe2 exchange reduced the payload only by 27% (0.58 × 10 −3 m B4A1/carrier) compared to the original conjugate. These observations are consistent with the computational simulations of interactions between B4A1 and Pep 1 (B4A1) . In 1:1 Pep 1 /B4A1 complexes the occurrence of π–π interactions between Phe1 and Phe2 with B4A1 arose most frequently and Lys7 plays a less dominant role.…”

“…Peptide‐PEG conjugates could render a large scope of problematic small molecule drugs water‐soluble. In this context, the concept has proved to be suitable for fluorescent and nonfluorescent, polar and nonpolar (experimental) drugs from major disease classes such as chlorin photosensitizers for photodynamic anticancer therapy or experimental TAU‐deaggregators for anti‐Alzheimer therapy as well as kinase inhibitors for potential anti‐malaria therapy . The peptide segment can be selected by combinatorial means identifying suitable sequences from large single bead‐single compound peptide libraries .…”

“…B4A1 lacks water solubility, suffers from low bioavailability, and is usually investigated in form of aqueous dimethyl sulfoxide (DMSO) solutions. A combinatorial screening selected a set of peptides from which two show effective solubilization of B4A1 as noncovalent drug complexes with peptide‐PEG conjugates (Pep 1 (B4A1)‐PEG and Pep 2 (B4A1)‐PEG, Figure ) . The drug conjugate complexes provide B4A1 in an available form for investigation in cell‐free TAU‐protein aggregation inhibition studies and cell‐based assays without requiring DMSO.…”

Secondary‐Structure‐Driven Self‐Assembly of Reactive Polypept(o)ides: Controlling Size, Shape, and Function of Core Cross‐Linked Nanostructures

“…Successful core cross-linking was confirmed by gel permeation chromatography in hexafluoro-2-propanol (HFIP), which is ag ood solvent for both blocks ( Figure S9). [39,40] As shown earlier, the cross-linking reaction (for c3 and c4 a-k after equimolar reduction with tris(2-carboxyethyl)phosphine (TCEP);Scheme S2) is independent of the chemical nature of the cross-linker and results in particles 9a-g with comparable size distributions ( Figure 3CII and Table S2). In addition to simply altering polarity,t he residues Ro ft he cross-linker c4 can be readily adjusted to match, for example,acertain cargo to covalently attach drugs or imaging probes.…”

Sekundärstrukturbildung als Triebkraft für die Selbstorganisation reaktiver Polypept(o)ide: Steuerung von Größe, Form und Funktion kernvernetzter Nanostrukturen

“…In Gegenwart von Thioharnstoff als chaotropem Agens liegen die PSar-b-PCys(SO 2 Et)-Polypept(o)ide hingegen als Knäuel vor,u nd der Selbstorganisationsprozess wird lediglich über das Volumenverhältnis zwischen hydrophilem und hydro- Außer fürd ie Steuerung der Morphologie und die kovalente Kernvernetzung ist die S-Alkylsulfonyl-Schutzgruppe in PSar-b-PCys(SO 2 Et)-Blockcopolymeren auch fürden Aufbau von Wirkstofftransportsystemen interessant. [39,40] Wieb ereits erwähnt, ist die Vernetzungsreaktion (für c3 und c4 a-k nach äquimolarer Reduktion mit Tris(2-carboxyethyl)phosphin (TCEP), Schema S2) unabhängig von der chemischen Natur des Vernetzers und resultiert in Partikeln 9a-g mit vergleichbaren Grçßenverteilungen (Abbildung 3C II und Tabelle S2). Es ist bekannt, dass disulfidvernetzte Mizellen und Polyplexe im Blut stabil sind (10 mm Glutathion (GSH)), im Zellinneren jedoch relativ schnell gespalten werden (10 mm GSH).…”