Multivalent Binding in the Design of Bioactive Compounds

Over the past several years, much research has centered on the development of small molecules that, through multivalent binding interactions, enhance the regulation of fundamental biological functions. The design of a wide range of potential therapeutics focuses on mimicking natural systems that control the biological effect of protein-ligand interactions through multivalency. In this review, the various approaches to achieving multivalency are discussed. Recent advances in the design of multivalent ligands are also presented. INTRODUCTION Many systems in nature rely on the properties of multivalency as a way to modulate the biological effect of protein-ligand interactions. In the past several years, these types of interactions have been exploited in the design of potential drug molecules. One of the reasons multiple binding interactions have evolved in nature is to increase the overall strength of interactions between a ligand and its The rational design of new therapeutic entities is always advanced by an increase in our understanding of the fundamental biological mechanisms responsible for modulation of potency and affinity. Over the past several years, biochemical studies have shown that the role of Fig. (1). Monovalent and bivalent interactions. multivalent interactions is fundamental to the regulation of many critical biological systems. The unique properties imparted through multivalent binding interactions have inspired a variety of new designs for small molecules that can modulate biological functions. Multivalent interactions, as defined in this review, will involve cases where the ligand has two exclusive binding domains that can simultaneously dock to two or more distinct sites either on the same receptor or on two distinct receptors (Fig. (1)). receptor. This can be an important mechanism to enhance the overall binding strength of a relatively low affinity ligand. Oligomers constructed of repeating units of low affinity ligands that can bind to a receptor containing multiple adjacent receptor sites can yield an overall strong interaction through an increase in avidity. These multiple interactions impart an overall higher avidity for the interaction of a weakly bound ligand and its receptor without increasing the affinity of the individual interactions (Fig. (2)). Perhaps the most well known of these effects are those that mediate the process of cellular adhesion where the interactions are driven primarily by high avidity imparted by *Address correspondence to this author at the 328 Chemistry Research Building, Department of Chemistry, University of Florida, Gainesville, FL 32601, USA; Ph.: +325-392-6787; Fax: +352-846-0296; e-mail: [email protected] 1385-2728/01 $20.00+.00 © 2001 Bentham Science Publishers Ltd. 1108 Current Organic Chemistry, 2001, Vol. 5, No. 11 Wright and Usher Fig. (2). High avidity interaction. the use of multiple binding events [1]. The thermodynamic profile of polyvalent interactions has been extensively treated in an excellent review by Whitesides and co-workers [2]. Molecules constructed with a second binding site would be expected to show an increase in affinity for the particular receptor or possibly an increase in selectivity since the second interaction may allow the ligand to discriminate between two structurally related receptors. A second type of multivalent interaction can occur when a ligand contains two separate binding domains that dock to two different sites on the same receptor. This type of interaction can increase the overall affinity since the equilibrium between association and dissociation of a ligand from one site on the receptor is greatly influenced by the second binding event at an adjacent site. A final classification for multivalent interactions can occur when a bivalent ligand can bind two different biomacromolecules, such as proteins, and bring them into contact [3]. This induced proximity mechanism can lead to cross-linking or clustering of receptors which has been Fig. (3). High affinity binding through bivalent interaction. Multivalent Binding in the Design of Bioactive Compounds Current Organic Chemistry, 2001, Vol. 5, No. 11 1109 Fig. (4). Bivalent ligand promotes receptor dimerization. demonstrated to be a key mechanism involved in a variety of signaling cascades (Fig. (4)). prompted a number of researchers to investigate this mode of action for the design of new therapeutic agents. Several molecules have been designed, synthesized and tested to take advantage of multivalent interactions to enhance affinity, increase avidity or induce proximity. This review will focus on small molecules that have been designed to capitalize on these effects to enhance the overall performance of a drug including issues of potency and selectivity. This type of interaction has been observed in a variety of biological systems such as the cross-linking of the receptor tyrosine kinase Trk A by nerve growth factor (NGF) which is present as a circulating homodimer [4]. The induced proximity of the two membrane bound receptors lead to phosphorylation of one kinase by the other and ultimately results in propagation of the signal induced by NGF. Several other growth factor based signaling systems have been studied and this type of interaction would appear to be quite general. INVESTIGATION OF MULTIVALENT LIGANDS An interesting study by LeBoullec and co-workers demonstrated the effectiveness of ligand homodimerization in increasing the selectivity and potency of a series of indole derivatives for certain members of the 5HT family of seretonergic receptor subtypes, 5HT1A and 5HT1D [5]. LeBoullec et al. showed that variations in the length of the Many studies relating to the molecular mechanisms of small-molecule/large-molecule interactions have shown that the use of two or more separate binding events can be used to control biological interactions. These studies have