Potent Inhibition of HIV‐1 Entry with a Chemically Programmed Antibody Aided by an Efficient Organocatalytic Synthesis

Gavrilyuk, Julia; Uehara, Hisatoshi; Otsubo, Nobumasa; Hessell, Ann J.; Burton, Dennis R.; Barbas, Carlos F.

doi:10.1002/cbic.201000432

Cited by 21 publications

(27 citation statements)

References 53 publications

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“…(110–112) This conjugate exhibited efficacy in a murine xenograft model of human prostate cancer (PC-3) and demonstrated up to a 45% inhibition of tumor growth versus controls. This antibody-attachment strategy has also been employed to minimize toxic side-effects of the HIV entry inhibitor Aplaviroc,(61) and to stabilize peptide-based targeting agents such as VEGF(77) and angiogenesis inhibitors of thrombospondin-1. (113) Indeed, a CovX-body containing a peptide-based angiopoietin-2 inhibitor (CVX-060) is currently being evaluated in a Phase II clinical trial in patients with advanced renal cell carcinoma.…”

Section: Cancermentioning

confidence: 99%

Antibody-Recruiting Molecules: An Emerging Paradigm for Engaging Immune Function in Treating Human Disease

et al. 2012

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Synthetic Immunology, the development of synthetic systems capable of modulating and/or manipulating immunological functions, represents an emerging field of research with manifold possibilities. One focus of this area has been to create low molecular-weight synthetic species, called antibody-recruiting molecules (ARMs), which are capable of enhancing antibody binding to disease-relevant cells or viruses, thus leading to their immune-mediated clearance. This article provides a thorough discussion of contributions in this area, beginning with the history of small-molecule-based technologies for modulating antibody recognition, followed by a systematic review of the various applications of ARM-based strategies. Thus, we describe ARMs capable of targeting cancer, bacteria, and viral pathogens, along with some of the scientific discoveries that have resulted from their development. Research in this area underscores the many exciting possibilities at the interface of organic chemistry and immunobiology, and is positioned to advance both basic and clinical science in the years to come.

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Section: Cancermentioning

confidence: 99%

Antibody-Recruiting Molecules: An Emerging Paradigm for Engaging Immune Function in Treating Human Disease

et al. 2012

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“…The cross-aldol reaction between methyl 4-oxobutyrate (110) and 3-methoxybenzaldehyde catalyzed by proline (20 mol%) was the key step in the synthesis of (−)-enterolactone (112) (Scheme 3.26) [158]. Furthermore, the cross-aldol reaction between phthalamidoacetaldehyde (81) and cyclohexanecarbaldehyde catalyzed by d-proline was used as the first step in the synthesis of a potent inhibitor of HIV-1, aplavirov [159].…”

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confidence: 99%

Organocatalyzed Aldol Reactions

Guillena¹

2013

Modern Methods in Stereoselective Aldol Reactions

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The use of catalytic enantioselective methods to perform an aldol reaction provides a direct entry for the synthesis of chiral compounds and is probably the most attractive way to achieve this goal with high control of the chemo-, regio-, diastereo-, and enantioselectivity. The application of biochemical methods based on enzyme aldolases or antibodies, which are discussed in other chapters, avoid the use of preformed enolates or their equivalents for enhancing the global atom efficiency of the process [1] for which the narrow substrate scope is a major drawback. The discovery of methodologies to carry out the enantioselective direct aldol reaction [2] has eluded the production of stoichiometric by-products increasing the substrate scope. This task could be accomplished by using small molecules as catalysts, such as metal complexes (which are covered along this book) and organic molecules, also known as organocatalysts [3]. The growth of this last research area and the direct aldol reaction are closely linked [4], with the report on the use of (S)-proline as catalyst for the intermolecular aldol [5] definitely being the push for the development of the organocatalytic methods as a competitive methodology for the synthesis of chiral compounds.In a strict sense, an organocatalyzed reaction is a process in which all the involved reagents and catalysis are purely organic compounds of low-molecular weight, excluding boron-and silicon-containing derivatives. However, in some cases, the presence of a silyl group only plays a steric role and therefore can also be considered as an organocatalyzed process. Also, if the organocatalyst involved in a reaction is immobilized in a polymer, a dendrimer, or even an inorganic material that serves only as a support to facilitate its recovery [6], it could still be considered as an organocatalyst, although those types of derivatives have been scarcely used in the natural product synthesis and therefore will be excluded from this chapter. Therefore, a comprehensive overview of the direct aldol reaction [7], emphasizing the reactivity, scope, selectivity, and limitations of the methodology and giving several examples of their application to the synthesis of biologically active compounds, is discussed in this chapter.

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“…Other non-integrin cell surface receptors with high affinity binding sites for small molecules that were derived by rational design or selected from chemical libraries have also been described as targets of cpAbs. This list includes prostate-specific membrane antigen (PSMA) [11], CCR5 [72], gp120 of HIV-1 [73], and neuraminidase of the influenza virus [74]. In addition, protein tyrosine kinase-7 and cell surface IgM have been targeted with cpAbs that deploy DNA aptamers as synthetic component [9].…”

Section: Applications Of Cpabsmentioning

confidence: 99%

Chemically programmed antibodies

Rader

2014

Trends in Biotechnology

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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 a virtually 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.

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Potent Inhibition of HIV‐1 Entry with a Chemically Programmed Antibody Aided by an Efficient Organocatalytic Synthesis

Cited by 21 publications

References 53 publications

Antibody-Recruiting Molecules: An Emerging Paradigm for Engaging Immune Function in Treating Human Disease

Antibody-Recruiting Molecules: An Emerging Paradigm for Engaging Immune Function in Treating Human Disease

Organocatalyzed Aldol Reactions

Chemically programmed antibodies

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