Druggable secondary sites in C-type lectin-like domains: Mechanistic insights and opportunities for chemical modulation.

C-type lectins are pivotal orchestrators of immunity and homeostasis. However, developing potent small molecule modulators remains a significant challenge, as their primary binding sites are shallow and solvent-exposed. Recent biophysical and computational advancements have revealed that the intrinsic structural plasticity of the C-type lectin-like domains can be leveraged to target these receptors through alternative sites with superior druggability. This review outlines recent progress on the discovery of secondary sites in C-type lectins and highlights mechanistic insights into first-in-class inhibitors and activators for the receptors DC-SIGN, langerin, NKG2D and LOX-1. Moreover, we discuss the conformational plasticity of the mannose receptor and MGL and the unexplored opportunities of targeting these receptors via secondary sites. By engaging these secondary sites, certain limitations of traditional glycomimetics can be circumvented, thereby expanding the druggable landscape of the CTL superfamily.