PMID- 34756012
OWN - NLM
STAT- MEDLINE
DCOM- 20220113
LR  - 20220113
IS  - 1520-4898 (Electronic)
IS  - 0001-4842 (Linking)
VI  - 54
IP  - 23
DP  - 2021 Dec 7
TI  - Therapeutic mRNA Engineering from Head to Tail.
PG  - 4272-4282
LID - 10.1021/acs.accounts.1c00541 [doi]
AB  - Synthetic messenger RNA (mRNA), once delivered into cells, can be readily 
      translated into proteins by ribosomes, which do not distinguish exogenous mRNAs 
      from endogenous transcripts. Until recently, the intrinsic instability and 
      immunostimulatory property of exogenous RNAs largely hindered the therapeutic 
      application of synthetic mRNAs. Thanks to major technological innovations, such 
      as introduction of chemically modified nucleosides, synthetic mRNAs have become 
      programmable therapeutic reagents. Compared to DNA or protein-based therapeutic 
      reagents, synthetic mRNAs bear several advantages: flexible design, easy 
      optimization, low-cost preparation, and scalable synthesis. Therapeutic mRNAs are 
      commonly designed to encode specific antigens to elicit organismal immune 
      response to pathogens like viruses, express functional proteins to replace 
      defective ones inside cells, or introduce novel enzymes to achieve unique 
      functions like genome editing. Recent years have witnessed stunning progress on 
      the development of mRNA vaccines against SARS-Cov2. This success is built upon 
      our fundamental understanding of mRNA metabolism and translational control, a 
      knowledge accumulated during the past several decades. Given the astronomical 
      number of sequence combinations of four nucleotides, sequence-dependent control 
      of mRNA translation remains incompletely understood. Rational design of synthetic 
      mRNAs with robust translation and optimal stability remains challenging. 
      Massively paralleled reporter assay (MPRA) has been proven to be powerful in 
      identifying sequence elements in controlling mRNA translatability and stability. 
      Indeed, a completely randomized sequence in 5' untranslated region (5'UTR) drives 
      a wide range of translational outputs. In this Account, we will discuss general 
      principles of mRNA translation in eukaryotic cells and elucidate the role of 
      coding and noncoding regions in the translational regulation. From the 
      therapeutic perspective, we will highlight the unique features of 5' cap, 5'UTR, 
      coding region (CDS), stop codon, 3'UTR, and poly(A) tail. By focusing on the 
      design strategies in mRNA engineering, we hope this Account will contribute to 
      the rational design of synthetic mRNAs with broad therapeutic potential.
FAU - Jia, Longfei
AU  - Jia L
AD  - Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, 
      United States.
FAU - Qian, Shu-Bing
AU  - Qian SB
AUID- ORCID: 0000-0002-4127-1136
AD  - Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, 
      United States.
LA  - eng
GR  - R01 GM122814/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20211110
PL  - United States
TA  - Acc Chem Res
JT  - Accounts of chemical research
JID - 0157313
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA, Viral)
RN  - 0 (mRNA Vaccines)
SB  - IM
MH  - *COVID-19
MH  - Humans
MH  - *Protein Biosynthesis/genetics
MH  - RNA, Messenger/genetics/metabolism
MH  - RNA, Viral
MH  - SARS-CoV-2
MH  - mRNA Vaccines
EDAT- 2021/11/11 06:00
MHDA- 2022/01/14 06:00
CRDT- 2021/11/10 13:04
PHST- 2021/11/11 06:00 [pubmed]
PHST- 2022/01/14 06:00 [medline]
PHST- 2021/11/10 13:04 [entrez]
AID - 10.1021/acs.accounts.1c00541 [doi]
PST - ppublish
SO  - Acc Chem Res. 2021 Dec 7;54(23):4272-4282. doi: 10.1021/acs.accounts.1c00541. 
      Epub 2021 Nov 10.