Programming an anti-flu strategy: A new and potent neuraminidase inhibitor that maintains long-term systemic exposure of an antibody and the therapeutic activity of the neuraminadase inhibitor zanamivir has been created. This strategy could provide a promising new class of influenza A drugs for therapy and prophylaxis, and validates enzyme inhibitors as programming agents in synthetic immunology.
[Show abstract][Hide abstract] ABSTRACT: Herein we describe the design and application of two small-molecule anti-HIV compounds for the creation of chemically programmed antibodies. N-acyl-β-lactam derivatives of two previously described molecules BMS-378806 and BMS-488043 that inhibit the interaction between HIV-1 gp120 and T-cells were synthesized and used to program the binding activity of aldolase antibody 38C2. Discovery of a successful linkage site to BMS-488043 allowed for the synthesis of chemically programmed antibodies with affinity for HIV-1 gp120 and potent HIV-1 neutralization activity. Derivation of a successful conjugation strategy for this family of HIV-1 entry inhibitors enables its application in chemically programmed antibodies and vaccines and may facilitate the development of novel bispecific antibodies and topical microbicides.
[Show abstract][Hide abstract] ABSTRACT: CCR5 antagonists are among the most advanced approaches in HIV therapy and may also be relevant to treatment of graft-versus-host disease and Staphylococcus aureus infection. To expand the potential of the only approved CCR5 antagonist, Maraviroc, we studied derivatives that would enable functional linkage of Maraviroc to long-lived carriers. Through targeted synthesis, we discovered an effective linkage site on Maraviroc and demonstrate the potential of these derivatives to prepare potent chemically programmed antibodies and PEGylated derivatives. The resulting compounds effectively neutralized a variety of HIV-1 isolates. Both chemically programmed antibody and PEGylation approaches extend the neutralization activity of serum circulating Maraviroc. Derivation of a successful conjugation strategy for Maraviroc should further enable its use in chemically programmed vaccines, novel bispecific antibodies, and topical microbicides.
[Show abstract][Hide abstract] ABSTRACT: Due to their unlimited chemical diversity, small molecules can rival monoclonal antibodies (mAbs) with respect to specificity and affinity for target molecules. However, key pharmacological properties of mAbs remain unmatched by small molecules. Chemical programming strategies have been developed for site-specific and covalent conjugation of small molecules to mAbs with unique reactivity centers. In addition to blending favorable features of small molecules and mAbs, chemically programmed antibodies (cpAbs) are economically attractive because they utilize the same mAb for an almost unlimited number of target molecule specificities, reducing manufacturing costs and shortening drug discovery and development time. Preclinical studies and clinical trials have begun to demonstrate the broad utility of cpAbs for the treatment and prevention of human diseases.
Trends in Biotechnology 03/2014; 32(4). DOI:10.1016/j.tibtech.2014.02.003 · 11.96 Impact Factor
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