Mirror-image ligand discovery enabled by single-shot fast-flow synthesis of D-proteins

被引：26

作者：

Callahan, Alex J. ^{[1
]}

Gandhesiri, Satish ^{[1
]}

Travaline, Tara L. ^{[2
]}

Reja, Rahi M. ^{[1
]}

Lozano Salazar, Lia ^{[1
]}

Hanna, Stephanie ^{[1
]}

Lee, Yen-Chun ^{[1
,9
]}

Li, Kunhua ^{[2
]}

Tokareva, Olena S. ^{[2
]}

Swiecicki, Jean-Marie ^{[2
,10
]}

Loas, Andrei ^{[1
]}

Verdine, Gregory L. ^{[2
,3
,4
,5
]}

Mcgee, John H. ^{[2
]}

Pentelute, Bradley L. ^{[1
,6
,7
,8
]}

机构：

[1] MIT, Dept Chem, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[2] FOG Pharmaceut Inc, 30 Acorn Pk Dr, Cambridge, MA 02140 USA

[3] Harvard Univ, Dept Stem Cell & Regenerat Biol, 7 Divin Ave, Cambridge, MA 02138 USA

[4] Harvard Univ, Dept Chem & Chem Biol, 12 Oxford St, Cambridge, MA 02138 USA

[5] Harvard Univ, Dept Mol & Cellular Biol, 52 Oxford St, Cambridge, MA 02138 USA

[6] MIT, Koch Inst Integrat Canc Res, 500 Main St, Cambridge, MA 02142 USA

[7] MIT, Ctr Environm Hlth Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[8] Broad Inst MIT & Harvard, 415 Main St, Cambridge, MA 02142 USA

[9] Natl Cheng Kung Univ, Dept Chem, 1 Univ Rd, Tainan 701, Taiwan

[10] Relay Therapeut, 399 Binney St, Cambridge, MA 02139 USA

来源：

NATURE COMMUNICATIONS | 2024年 / 15卷 / 01期

关键词：

D-PEPTIDE INHIBITORS; E3 UBIQUITIN LIGASE; D-AMINO-ACID; P53-MDM2; INTERACTION; CHEMICAL-SYNTHESIS; SH2; DOMAIN; CHIP; TARGET; IDENTIFICATION; TRANSCRIPTION;

D O I：

10.1038/s41467-024-45634-z

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Widespread adoption of mirror-image biological systems presents difficulties in accessing the requisite D-protein substrates. In particular, mirror-image phage display has the potential for high-throughput generation of biologically stable macrocyclic D-peptide binders with potentially unique recognition modes but is hindered by the individualized optimization required for D-protein chemical synthesis. We demonstrate a general mirror-image phage display pipeline that utilizes automated flow peptide synthesis to prepare D-proteins in a single run. With this approach, we prepare and characterize 12 D-proteins - almost one third of all reported D-proteins to date. With access to mirror-image protein targets, we describe the successful discovery of six macrocyclic D-peptide binders: three to the oncoprotein MDM2, and three to the E3 ubiquitin ligase CHIP. Reliable production of mirror-image proteins can unlock the full potential of D-peptide drug discovery and streamline the study of mirror-image biology more broadly. Mirror-image phage display has the potential for high-throughput generation of biologically stable macrocyclic D-peptide binders but is hindered by the optimization required for D-protein chemical synthesis. Here, the authors report a general mirror-image phage display pipeline based on automated flow peptide synthesis and use it to prepare and characterize 12 L/D-protein pairs.

引用

页数：13

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