RNA Drugs and RNA Targets for Small Molecules: Principles, Progress, and Challenges
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1521-0081/72/4/862–898$35.00 https://doi.org/10.1124/pr.120.019554 PHARMACOLOGICAL REVIEWS Pharmacol Rev 72:862–898, October 2020 Copyright © 2020 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. ASSOCIATE EDITOR: RHIAN M. TOUYZ RNA Drugs and RNA Targets for Small Molecules: Principles, Progress, and Challenges Ai-Ming Yu, Young Hee Choi, and Mei-Juan Tu Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Sacramento, California (A.-M.Y., Y.H.C., M.-J.T.) and College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Gyonggi-do, Republic of Korea (Y.H.C.) Abstract. ....................................................................................863 Significance Statement ......................................................................863 I. Introduction. ..............................................................................863 II. Classification and General Features of RNA-Based Therapeutics .............................864 III. RNAs as Therapeutic Drugs .................................................................865 A. The Rise and Promise of RNA Therapeutics ..............................................865 B. Types of RNA Drugs and Mechanisms of Action ..........................................866 1. Antisense Oligonucleotides ...........................................................866 Downloaded from 2. Small Interfering RNAs . ............................................................868 3. MicroRNAs. ........................................................................870 4. RNA Aptamers .......................................................................871 5. Messenger RNAs . ..................................................................872 6. Guide RNAs. ........................................................................874 by guest on September 25, 2021 7. Other Forms of RNAs ................................................................874 C. Challenges in the Development of RNA Drugs. ..........................................875 1. Choice of RNA Substances ............................................................875 2. RNA Delivery Systems . ............................................................877 3. RNA Analytical Methods . ............................................................878 4. Specificity and Safety of RNA Drugs . ................................................879 IV. RNAs as Therapeutic Targets for Small Molecules . ..........................................880 A. Small Molecules Targeting Highly Structured RNAs. .....................................880 B. Classes of RNA Targets..................................................................883 1. Ribosomal RNAs . ..................................................................883 2. Viral RNA Motifs. ..................................................................884 3. Riboswitches . ........................................................................886 4. Precursor Messenger RNAs ...........................................................887 5. Primary and Precursor MicroRNAs . ................................................887 6. Other RNA Targets. ..................................................................888 C. Challenges in the Discovery and Development of RNA-Targeted Small-Molecule Drugs . 889 1. Identification of Druggable RNA Targets ..............................................889 2. Specificity in Targeting RNAs . ......................................................889 V. Conclusions and Perspectives ................................................................890 References ..................................................................................890 Address correspondence to: Dr. Ai-Ming Yu, Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, 2700 Stockton Blvd. Suite 2132, Oak Park Research Building, Sacramento, CA 95817. E-mail: [email protected]; or Dr. Young Hee Choi, College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, 32 Dongguk-lo, Ilsandong-gu, Goyang-si, Gyeonggi-do 10326, Republic of Korea. E-mail: [email protected] A.-M.Y. was funded by National Institutes of Health National Cancer Institute [Grant R01-CA225958] and National Institute of General Medical Sciences [Grant R01GM113888]. Y.H.C. was supported by the National Research Foundation of Korea grants funded by the Korea government (MIST) [NRF-2016R1C1B2010849 and NRF-2018R1A5A2023127]. https://doi.org/10.1124/pr.120.019554. 862 RNA-Based Therapies 863 Abstract——RNA-based therapies, including RNA or synthetic antibiotics (e.g., aminoglycosides, tetracyclines, molecules as drugs and RNA-targeted small molecules, macrolides, oxazolidinones, and phenicols) can directly offer unique opportunities to expand the range of bind to ribosomal RNAs to achieve the inhibition of therapeutic targets. Various forms of RNAs may be bacterial infections. Therefore, there is growing interest in used to selectively act on proteins, transcripts, and developing RNA-targeted small-molecule drugs amenable genes that cannot be targeted by conventional small to oral administration, and some (e.g., risdiplam and molecules or proteins. Although development of RNA branaplam) have entered clinical trials. Here, we review drugs faces unparalleled challenges, many strategies the pharmacology of novel RNA drugs and RNA-targeted have been developed to improve RNA metabolic stability small-molecule medications, with a focus on recent and intracellular delivery. A number of RNA drugs progresses and strategies. Challenges in the development have been approved for medical use, including aptamers of novel druggable RNA entities and identification of (e.g., pegaptanib) that mechanistically act on protein viable RNA targets and selective small-molecule binders target and small interfering RNAs (e.g., patisiran and are discussed. givosiran) and antisense oligonucleotides (e.g., inotersen and golodirsen) that directly interfere with RNA targets. Significance Statement——With the understanding Furthermore, guide RNAs are essential components of of RNA functions and critical roles in diseases, as well novel gene editing modalities, and mRNA therapeutics as the development of RNA-related technologies, there are under development for protein replacement therapy is growing interest in developing novel RNA-based or vaccination, including those against unprecedented therapeutics. This comprehensive review presents severe acute respiratory syndrome coronavirus pandemic. pharmacology of both RNA drugs and RNA-targeted Moreover, functional RNAs or RNA motifs are highly small-molecule medications, focusing on novel mechanisms structured to form binding pockets or clefts that are of action, the most recent progress, and existing accessible by small molecules. Many natural, semisynthetic, challenges. I. Introduction such as aptamers, antisense oligonucleotides (ASO), small interfering RNAs (siRNA), and guide RNAs Therapeutic drugs act on corresponding molecular (gRNA), have emerged as a new class of modalities in targets, biological pathways, or cellular processes clinical practice and are under active development to elicit pharmacological effects for the treatment of human diseases. Small-molecule compounds and pro- (Crooke et al., 2018; Yin and Rogge, 2019; Yu et al., teins/antibodies remain as the major forms of medi- 2019); RNA molecules may act not only on conven- cations for medical use and the preferred modalities tional proteome but also on previously undrugged in drug development, acting mainly on protein targets transcriptome, including mRNAs to be translated such as enzymes, receptors, ion channels, transport- into proteins and functional noncoding RNAs (ncRNAs) ers, and kinases (Santos et al., 2017; Usmani et al., which largely outnumber mRNAs (Mattick, 2004; 2017; Rock and Foti, 2019; Yin and Rogge, 2019). With Djebali et al., 2012), as well as the genome. More- unique physicochemical and pharmacological character- over, some mRNAs and ncRNAs, such as microRNAs istics complementary to traditional protein-targeted (miRNA or miR), are also under preclinical and clinical small-molecule and protein drugs (Table 1), RNA molecules, development for replacement therapy or vaccination ABBREVIATIONS: A, adenine; AHP, acute hepatic porphyria; ALA, d-aminolevulinic acid; ALAS1, d-ALA synthase 1; AMD, age-related macular degeneration; ApoB, apolipoprotein B; A-site, aminoacyl-tRNA site; ASO, antisense oligonucleotide; asRNA, antisense RNA; BERA, bioengineered or biological RNA agents; C, cytosine; Cas, CRISPR-associated protein; DC, dendritic cell; DMD, Duchenne muscular dystro- phy; DPQ, 6,7-dimethoxy-2-(1-piperazinyl)-4-quinazolinamine; dsRNA, double-stranded RNA; EphA2, ephrin type-A receptor 2; E-site, exit site; EWS, Ewing sarcoma breakpoint region 1; FDA, Food and Drug Administration; FL, fluorescence; FLI1, Friend leukemia integration 1 transcription factor; FLT-1, fms-like tyrosine kinase; FMN, flavin mononucleotide; G, guanine; GalNAc, N-acetylgalactosamine; gRNA, guide RNA; hATTR amyloidosis, hereditary transthyretin-mediated amyloidosis; HCV, hepatitis C virus; HD, Huntington disease; HIV, human immunodeficiency virus; HoFH, homozygous familial hypercholesterolemia; HPLC, high-performance liquid chromatography; HTT, hun- tingtin; IL, interleukin; IRES, internal ribosome entry site; IVT, in vitro–transcribed;