Recent advances on the inhibition of human solute carriers: Therapeutic implications and mechanistic insights

Abstract

Solute carriers (SLCs) are membrane transport proteins tasked with mediating passage of hydrophilic molecules across lipid bilayers. Despite the extensive roles played in all aspects of human biology, SLCs remain vastly under-explored as therapeutic targets. In this brief review, we first discuss a few successful cases of drugs that exert their mechanisms of action through inhibition of human SLCs, and introduce select examples of human SLCs that have untapped therapeutic potential. We then highlight two recent structural studies which uncovered detailed structural mechanisms of inhibition exhibited against two different human major facilitator superfamily (MFS) transporters of clinical relevance.

Figure 1

Overview of the function and clinical relevance of inhibition for (a) hMCT1 and (b) hENT1. (c) Cryo-electron microscopy structures of hMCT1 in complex with inhibitors AZD3965, BAY-8002, and 7ACC2 (PDB IDs 6LYY, 7CKR, 7CKO, respectively). (d) X-ray crystal structures of hENT1 in complex with inhibitors dilazep and NBMPR (PDB IDs 6OB7, 6OB6, respectively).

Figure 2

(a) Surface representation of hMCT1 or hENT1 in complex with inhibitions. (b) Detailed transporter-inhibitor interactions, with key residues depicted as sticks. (c) Experimental ligand densities. Cryo-EM densities depicted at a map threshold of 0.5 for hMCT1 bound to AZD3965, BAY-8002 or 7ACC2 (EMDB IDs EMD-30019, EMD-30391, EMD-30389). X-ray crystal structure electron densities depicted at 1.5σ from the final 2F_o-F_c maps for hENT1 bound to dilazep or NBMPR (PDB IDs 6OB7, 6OB6).

Figure 3

Inhibitory mechanisms in the context of a generalized transport mechanism (rocker-switch) for major facilitator superfamily transporters. Dilazep, AZD3965 and BAY-8002 inhibit transport by simultaneously occupying the substrate binding site while contacting key elements of TM1 and TM7, which interferes with extracellular gate closure. In contrast, NBMPR prevents the transition from outward occluded to inward occluded states by interfering with conformational rearrangements in the N-domain, while 7ACC2 appears to arrest the inward-facing state by preventing intracellular gate closure through contacting key elements of TM10.