Automated Flow Synthesis of Peptide-PNA Conjugates

被引：23

作者：

Li, Chengxi ^{[1
]}

Callahan, Alex J. ^{[1
]}

Phadke, Kruttika S. ^{[2
]}

Bellaire, Bryan ^{[2
]}

Farquhar, Charlotte E. ^{[1
]}

Zhang, Genwei ^{[1
]}

Schissel, Carly K. ^{[1
]}

Mijalis, Alexander J. ^{[1
]}

Hartrampf, Nina ^{[1
,3
]}

Loas, Andrei ^{[1
]}

Verhoeven, David E. ^{[2
]}

Pentelute, Bradley L. ^{[1
,4
,5
,6
]}

机构：

[1] MIT, Dept Chem, Cambridge, MA 02139 USA

[2] Iowa State Univ, Coll Vet Med, Dept Vet Microbiol & Prevent Med, Ames, IA 50011 USA

[3] Univ Zurich, Dept Chem, Wintherthurerstr 190, CH-8057 Zurich, Switzerland

[4] MIT, Ctr Environm Hlth Sci, Cambridge, MA 02139 USA

[5] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02142 USA

[6] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

来源：

ACS CENTRAL SCIENCE | 2022年 / 8卷 / 02期

基金：

美国国家科学基金会;

关键词：

ANTISENSE MORPHOLINO-OLIGOMERS; NUCLEIC-ACIDS; OLIGONUCLEOTIDES; CELLS;

D O I：

10.1021/acscentsci.1c01019

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Antisense peptide nucleic acids (PNAs) have yet to translate to the clinic because of poor cellular uptake, limited solubility, and rapid elimination. Cell-penetrating peptides (CPPs) covalently attached to PNAs may facilitate clinical development by improving uptake into cells. We report an efficient technology that utilizes a fully automated fast -flow instrument to manufacture CPP-conjugated PNAs (PPNAs) in a single shot. The machine is rapid, with each amide bond being formed in 10 s. Anti-IVS2-654 PPNA synthesized with this instrument presented threefold activity compared to transfected PNA in a splice-correction assay. We demonstrated the utility of this approach by chemically synthesizing eight anti-SARS-CoV-2 PPNAs in 1 day. A PPNA targeting the 5 ' untranslated region of SARS-CoV-2 genomic RNA reduced the viral titer by over 95% in a live virus infection assay (IC50 = 0.8 mu M). Our technology can deliver PPNA candidates to further investigate their potential as antiviral agents.

引用

页码：205 / 213

页数：9

共 47 条

[1] Interference of ribosomal frameshifting by antisense peptide nucleic acids suppresses SARS coronavirus replication [J].