Jon A. Ashley

Phosphonamidates and phosphonamidate esters as HIV-1 protease inhibitors

Simple dipeptides incorporating phosphonamidate and phosphonamidate ester isosteres for the scissile peptide bond are modest inhibitors of the HIV-1 protease. Their synthesis and inhibition studies are described.

Cocaine catalytic antibodies: the primary importance of linker effects.

Current treatments for cocaine addiction are not effective. The development of a catalytic monoclonal antibody (mAb) provides a strategy for not only binding, but also degrading cocaine, which offers a broad-based therapy. Hapten design is the central element for programming antibody catalysis. The characteristics of the linker used in classic transition-state analogue phosphonate haptens were shown to be important for obtaining mAbs that hydrolyze the benzoate ester of cocaine.

Monitoring Chemical Warfare Agents: A New Method for the Detection of Methylphosphonic Acid

Methylphosphonic acid (MPA) is the degradation product of many chemical warfare agents. The convenient detection of this substance would aid in field testing to confirm illicit manufacture and use of banned chemical weapons. Efficient functionalization of MPA with an aromatic diazo compound allowed binding by monoclonal antibodies elicited by using an analogous hapten (see scheme). An ELISA assay was rapid, sensitive, and specific.

Convenient synthesis of L-proline benzyl ester.

Mesylates or tosylates of delta-hydroxy-L-norvaline esters spontaneously afford L-proline esters upon exposure to aqueous buffer in near quantitative yield. This novel reaction has led to the development of a simple route to optically active proline esters.

Nachweis chemischer Kampfstoffe anhand des Abbauprodukts Methylphosphonsäure

Methylphosphonsaure (MPA) ist das Abbauprodukt vieler chemischer Kampfstoffe. Ihr einfacher Nachweis ware bei Gelandeuntersuchungen hilfreich, um die illegale Herstellung und den Einsatz verbotener chemischer Waffen nachzuweisen. MPA lies sich effektiv mit einer aromatischen Diazoverbindung funktionalisieren, und das dabei erhaltene Derivat wurde von monoklonalen Antikorpern gebunden, die mit Hilfe eines analogen Haptens erzeugt worden waren (siehe Schema). Die Messung mittels ELISA war schnell, empfindlich und spezifisch.

Antibody-catalyzed cleavage of the D-Ala-D-Lac depsipeptide: an immunological approach to the problem of vancomycin resistance.

Vancomycin resistance is currently a major healthcare problem. The development of a catalytic monoclonal antibody (mAb) that hydrolyzes the D-Ala-D-Lac depsipeptide provides a potentially novel antibiotic strategy. A phosphonate hapten design was used to program antibody catalysis. The characteristics of the hapten were shown to be important for obtaining a viable immune response and several catalytic mAbs that cleave a peptidoglycan model substrate. The best mAb afforded a >500-fold rate enhancement over background.

Reactive immunization elicits catalytic antibodies for polyester hydrolysis

In the search for biocatalysts for degradation of nonnatural polymers, reactive immunization with haptens 7 and 11 was used to prepare catalytic antibodies capable of cleaving short oligomeric esters, as well as the insoluble polyester 25. These antibodies were found to be highly specific and efficient esterases for oligomers. Triester 24 was preferentially hydrolyzed by an endo-cleavage pathway, however, with a higher molecular weight polymer 25 no site specificity could be observed. Catalytic efficiency of the antibodies towards the insoluble polymer 25 was limited due to physical constraints.

The α-ketoamide group: a new motif for the elicitation of catalytic antibodies for acyl-transfer reactions

An α-ketoamide hapten elicited a monoclonal antibody that catalyzed the hydrolyses of esters and carbamates via either a covalent intermediate or direct addition of water.