Structure–Activity Relationship Study on Col-003, a Protein–Protein Interaction Inhibitor between Collagen and Hsp47

Abstract

This study demonstrates the structure-activity relationship of Col-003, a potent collagen-heat-shock protein 47 (Hsp47) interaction inhibitor. Col-003 analogues were successfully synthesized by Pd(0)-catalyzed cross-coupling reactions of 5-bromosalicylaldehyde derivatives with alkyl-metal species, and the inhibitory activities of the synthetic analogues were evaluated using surface plasmon resonance analysis (BIAcore). We succeeded in discovering two potent inhibitors that showed 85 and 81% inhibition at a concentration of 1.9 µM against the collagen-Hsp47 interaction. This indicates that elongation of an alkyl linker between two aromatic rings could considerably improve inhibitory activity due to the adjustment of a pendant phenyl moiety to an appropriate position, in addition to the hydrophobic interaction with an alkyl linker moiety.

A BRET-based assay reveals collagen–Hsp47 interaction dynamics in the endoplasmic reticulum and small-molecule inhibition of this interaction

“…The Col003 compound was synthesized as previously reported (4). The synthesis of Col049, Col050, and Col051 is described in the study (27), where Col049, Col050, and Col051 refers to 5eE, 5eF, and 5eG, respectively.…”

HSP47: A Therapeutic Target in Pulmonary Fibrosis

“…Subsequently, they synthesized Col003 via Pd(0)-catalyzed cross-coupling reactions of 5-bromosalicylaldehyde derivatives with alkyl metal species. Two potent inhibitors were discovered that inhibited the interaction between collagen and HSP47 by 85% and 81%, respectively, at a concentration of 1.9 µM [ 99 ].…”

Identification of HSP47 Binding Site on Native Collagen and Its Implications for the Development of HSP47 Inhibitors

“…After initial screening, we manually selected 58 compounds for subsequent inhibitory activity assay according to the diversity and potential interactive mechanisms between the compounds and HSP47. Collagen molecules in a buffer of physiological pH spontaneously associated to form fibrils [17,35,36], while the turbidity gradually increased in a concentration-dependent manner and then reached a plateau phase (Figure 4a). HSP47 retarded this fibril formation process within the range of 2.0-5.2 µM (Figure 4b).…”

“…The docking grid box was defined to include the whole collagen binding region on the HSP47 surface. Apart from Com II, Hs1, and Hs55, a recently identified HSP47 inhibitor Col003 and its analogues were also selected for docking [20,36]. The docking results indicated that Com II and Col003 bind to the surface area of HSP47 involved in binding the GXR motif of collagen (colored yellow in Figure 5, subpocket1).…”