Improving potencies and properties of CD4 down-modulating CADA analogs

Author： Bell Thomas W Demillo Violeta G Schols Dominique Vermeire Kurt

ISSN： 1746-0441

Source： Expert Opinion on Drug Discovery, Vol.7, Iss.1, 2012-01, pp. : 39-48

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Abstract

Introduction: CADA is a synthetic small molecule that inhibits HIV replication in cell cultures through down-modulating cell surface CD4 by inhibiting cotranslational translocation of nascent CD4 across the ER membrane in a signal sequence-specific manner. Analogs have been prepared mainly to increase potency and investigate the mechanism of action. Areas covered: This article reviews progress on discovery of more potent CADA analogs, including symmetrical and unsymmetrical compounds, as well as fluorescent derivatives. The article also discusses some properties of CADA and a more potent analog (KKD023) that are relevant to drug development, including aqueous solubility, permeability, metabolism and oral bioavailability. Expert opinion: Further studies on CADA analogs should focus on improving both potency and drug-like properties, and on elucidating the detailed mechanism of action. Solubility and permeability may be improved by reducing molecular weight, decreasing molecular flexibility and symmetry, or by a prodrug approach inducing active transport. Identifying the molecular mechanism of CD4 down-modulation may aid in assessing potential side effects of such immunomodulatory/anti-HIV drugs, and it could potentially lead to a general approach to designing drugs for specifically down-modulating other cell-surface proteins.