Design of tRNA<sup>Lys</sup><sub>3</sub> Ligands: Fragment Evolution and Linker Selection Guided by NMR Spectroscopy

Chung, Florence; Tisné, Carine; Lecourt, Thomas; Seijo, Bili; Dardel, Frédéric; Micouin, Laurent

doi:10.1002/chem.200802451

Cited by 20 publications

(9 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Disrupting its interaction with the HIV-1 genome inhibits viral replication, making tRNA Lys3 a potential antiviral target [49]. tRNA Lys3 was thus targeted using an NMR fragment-based screen with 50 initial compounds [50]. The screen identified two compounds with K D values of 1 and 5 mM.…”

Section: Trends In Pharmacological Sciencesmentioning

confidence: 99%

Screening strategies for identifying RNA- and ribonucleoprotein-targeted compounds

Martin

Grandi

Marcia

2021

Trends in Pharmacological Sciences

View full text Add to dashboard Cite

The past few years have witnessed important breakthroughs in the identification of compounds that specifically bind and regulate RNAs and in optimizing them for therapeutic use. Here, we review successful and unsuccessful approaches in screening for RNA-targeted small molecules. We discuss advantages and disadvantages of the different screening techniques and variables that affect the outcome of RNA-screening projects. We also highlight key challenges that hamper the development of quality RNA ligands, especially the still-low availability of RNA-specific compound libraries and the poor understanding of RNA structural dynamics. We conclude that the development of new RNA-targeting drugs would greatly benefit from integration of the power of high-throughput screening technologies with improved biochemical, structural, and computational characterization of RNA targets. The unique challenges of discovering drugs against RNAAs a messenger of genetic information, a catalyzer of biological reactions like splicing or protein synthesis, a transcriptional and translational regulator, and a modulator of metabolic proteins, RNA participates in fundamental physiopathological processes in cells [1]. Intervening in RNA with small molecules could thus be a powerful way to treat human diseases [1]. RNA-binding molecules have played important roles in medicine since the 1940s, when aminoglycoside antibiotics, which target rRNA, were discovered through unbiased phenotypic and genetic screens [2]. However, aminoglycosides tend to bind RNA promiscuously, which limits their applicability [3], so to achieve selective and potent targeting of RNAs it is important to enlarge the chemical space of RNA-binding compounds.The recent discovery of many new, vast classes of RNAs, such as riboswitches and long noncoding RNAs (lncRNAs), some of which adopt well-defined functional structures, has now expanded the universe of potentially druggable RNAs [4][5][6]. However, the development of drugs against RNA presents unique challenges (Box 1). Drug discovery focused on RNA targets consequently lags behind drug discovery aimed at protein targets [2] . Besides the structural and chemical properties of protein versus RNA ligands, which have been reviewed elsewhere [2,7], the design and implementation of screening strategies optimized for RNA are crucial factors contributing to successful RNA drug discovery (Figure 1).Screening design: the choice of a suitable RNA target RNA-focused screens seek to identify compounds that target RNA either directly or within ribonucleoprotein (RNP) (see Glossary) complexes. RNA-specific drugs have the potential to provide new therapeutic opportunities for diseases where protein targeting is difficult (i.e., genetic disorders associated with aberrant transcripts) or for infectious diseases. However, targeting RNA directly may be challenging if transcripts are expressed at low levels or lack structured regions. RNPs, which are being rapidly discovered thanks to proteomics and crosslinking and immunoprecipitation (CLIP)-b...

show abstract

Section: Trends In Pharmacological Sciencesmentioning

confidence: 99%

Screening strategies for identifying RNA- and ribonucleoprotein-targeted compounds

Martin

Grandi

Marcia

2021

Trends in Pharmacological Sciences

View full text Add to dashboard Cite

show abstract

“…All three peptides were found to recognize the 3D structure of the D-stem and loop of tRNAs [152]. Compounds were further optimized for tRNA 3 Lys binding [153,154]; their effect on initiation of reverse transcription needs now to be tested.…”

Section: Initiation Of Reverse Transcription As a Drug Targetmentioning

confidence: 99%

Initiation of HIV Reverse Transcription

Isel

Ehresmann

Marquet

2010

Viruses

View full text Add to dashboard Cite

Reverse transcription of retroviral genomes into double stranded DNA is a key event for viral replication. The very first stage of HIV reverse transcription, the initiation step, involves viral and cellular partners that are selectively packaged into the viral particle, leading to an RNA/protein complex with very specific structural and functional features, some of which being, in the case of HIV-1, linked to particular isolates. Recent understanding of the tight spatio-temporal regulation of reverse transcription and its importance for viral infectivity further points toward reverse transcription and potentially its initiation step as an important drug target.

show abstract

“…How to covalently link[62–66] two distinct fragments that bind in close proximity at adjacent sites on a protein is a fundamentally difficult and mostly unsolved problem in FBDD. Linking is an error-prone task that can easily reduce or eliminate the affinity of the larger di-fragment (fragment pair).…”

Section: Results: Computational Gamess/resp Calculations On the Pcsk9mentioning

confidence: 99%

Fragment-based design of small molecule PCSK9 inhibitors using simulated annealing of chemical potential simulations

Guarnieri

Kulp²,

Cloudsdale³

2019

PLoS ONE

View full text Add to dashboard Cite

PCSK9 is a protein secreted by the liver that binds to the low-density lipoprotein receptor (LDLR), causing LDLR internalization, decreasing the clearance of circulating LDL particles. Mutations in PCSK9 that strengthen its interactions with LDLR result in familial hypercholesterolemia (FH) and early onset atherosclerosis, while nonsense mutations of PCSK9 result in cardio-protective hypocholesterolemia. These observations led to PCSK9 inhibition for cholesterol lowering becoming a high-interest therapeutic target, with antibody drugs reaching the market. An orally-available small molecule drug is highly desirable, but inhibiting the PCSK9/LDLR protein-protein interaction (PPI) has proven challenging. Alternate approaches to finding good lead candidates are needed. Motivated by the FH mutation data on PCSK9, we found that modeling the PCSK9/LDLR interface revealed extensive electron delocalization between and within the protein partners. Based on this, we hypothesized that compounds assembled from chemical fragments could achieve the affinity required to inhibit the PCSK9/LDLR PPI if they were selected to interact with PCSK9 in a way that, like LDLR, also involves significant fractional charge transfer to form partially covalent bonds. To identify such fragments, Simulated Annealing of Chemical Potential (SACP) fragment simulations were run on multiple PCSK9 structures, using optimized partial charges for the protein. We designed a small molecule, composed of several fragments, predicted to interact at two sites on the PCSK9. This compound inhibits the PPI with 1 μM affinity. Further, we designed two similar small molecules where one allows charge delocalization though a linker and the other doesn’t. The first inhibitor with charge delocalization enhances LDLR surface expression by 60% at 10 nM, two orders of magnitude more potent than the EGF domain of LDLR. The other enhances LDLR expression by only 50% at 1 μM. This supports our conjecture that fragments can have surprisingly outsized efficacy in breaking PPI’s by achieving fractional charge transfer leading to partially covalent bonding.

show abstract

Design of tRNA^Lys₃ Ligands: Fragment Evolution and Linker Selection Guided by NMR Spectroscopy

Cited by 20 publications

References 33 publications

Screening strategies for identifying RNA- and ribonucleoprotein-targeted compounds

Screening strategies for identifying RNA- and ribonucleoprotein-targeted compounds

Initiation of HIV Reverse Transcription

Fragment-based design of small molecule PCSK9 inhibitors using simulated annealing of chemical potential simulations

Contact Info

Product

Resources

About

Design of tRNALys3 Ligands: Fragment Evolution and Linker Selection Guided by NMR Spectroscopy

Cited by 20 publications

References 33 publications

Screening strategies for identifying RNA- and ribonucleoprotein-targeted compounds

Screening strategies for identifying RNA- and ribonucleoprotein-targeted compounds

Initiation of HIV Reverse Transcription

Fragment-based design of small molecule PCSK9 inhibitors using simulated annealing of chemical potential simulations

Contact Info

Product

Resources

About

Design of tRNA^Lys₃ Ligands: Fragment Evolution and Linker Selection Guided by NMR Spectroscopy