Use Of Electrophiles Research Articles

Histidine-Covalent Stapled Alpha-Helical Peptides Targeting hMcl-1.

Several novel and effective cysteine targeting (Cys) covalent drugs are in clinical use. However, the target area containing a druggable Cys residue is limited. Therefore, methods for creating covalent drugs that target different residues are being looked for; examples of such ligands include those that target the residues lysine (Lys) and tyrosine (Tyr). Though the histidine (His) side chain is more frequently found in protein binding locations and has higher desirable nucleophilicity, surprisingly limited research has been done to specifically target this residue, and there are not many examples of His-targeting ligands that have been rationally designed. In the current work, we created novel stapled peptides that are intended to target hMcl-1 His 252 covalently. We describe the in vitro (biochemical, NMR, and X-ray) and cellular design and characterization of such agents. Our findings further suggest that the use of electrophiles to specifically target His residues is warranted.

Efficient Targeted Degradation via Reversible and Irreversible Covalent PROTACs.

Proteolysis targeting chimeras (PROTACs) represent an exciting inhibitory modality with many advantages, including substoichiometric degradation of targets. Their scope, though, is still limited to date by the requirement for a sufficiently potent target binder. A solution that proved useful in tackling challenging targets is the use of electrophiles to allow irreversible binding to the target. However, such binding will negate the catalytic nature of PROTACs. Reversible covalent PROTACs potentially offer the best of both worlds. They possess the potency and selectivity associated with the formation of the covalent bond, while being able to dissociate and regenerate once the protein target is degraded. Using Bruton’s tyrosine kinase (BTK) as a clinically relevant model system, we show efficient degradation by noncovalent, irreversible covalent, and reversible covalent PROTACs, with <10 nM DC50’s and >85% degradation. Our data suggest that part of the degradation by our irreversible covalent PROTACs is driven by reversible binding prior to covalent bond formation, while the reversible covalent PROTACs drive degradation primarily by covalent engagement. The PROTACs showed enhanced inhibition of B cell activation compared to ibrutinib and exhibit potent degradation of BTK in patient-derived primary chronic lymphocytic leukemia cells. The most potent reversible covalent PROTAC, RC-3, exhibited enhanced selectivity toward BTK compared to noncovalent and irreversible covalent PROTACs. These compounds may pave the way for the design of covalent PROTACs for a wide variety of challenging targets.

Polypeptide End-Capping Using Functionalized Isocyanates: Preparation of Pentablock Copolymers

The use of electrophiles (isocyanates, isothiocyanates, acid chlorides) to cap the N-terminal ends of polypeptides and the use of isocyanates to prepare poly(γ-benzyl-l-glutamate)-b-(nonpeptide pol...

ChemInform Abstract: Macrocyclic Receptor Molecules for Urea: The Use of Electrophiles in the (Co)complexation of Neutral Molecules.

AbstractThe crown ethers (I) and (II) are synthesized by known methods.

Macrocyclic receptor molecules for urea: the use of electrophiles in the (co-)complexation of neutral molecules

On montre que des electrophiles comme Li + ou H + sont des especes pontantes vitales dans la cocomplexation d'invites neutres par des ethers crown