From Screening to Targeted Degradation: Strategies for the Discovery and Optimization of Small Molecule Ligands for PCSK9

Petrilli, Whitney L.; Adam, Gregory C.; Erdmann, Roman S.; Abeywickrema, Pravien; Agnani, Vijayalakshmi; Ai, Xi; Baysarowich, Jennifer; Byrne, Noel; Caldwell, John P.; Chang, Wonsuk; DiNunzio, Edward; Feng, Zhe Chuan; Ford, Ralph V.; Ha, Sookhee; Huang, Yunxin; Hubbard, Bryn; Johnston, Jennifer M.; Kavana, Michael; Lisnock, JeanMarie; Li, Rui; Lu, Zhiqu; Meng, Juncai; Orth, Peter P.; Palyha, Oksana; Parthasarathy, Gopal; Salowe, Scott P.; Sharma, Sunil; Shipman, Jennifer M.; Soisson, S.M.; Strack, AlisonM.; Youm, Hyewon; Zhao, Kake; Zink, Deborah L.; Zokian, Hratch; Addona, George H.; Akinsanya, Karen; Tata, James R.; Xiong, Yusheng; Imbriglio, Jason E.

doi:10.1016/j.chembiol.2021.01.019

Cited by 4 publications

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“…PCSK9 is a serine protease with protein–protein interaction with the LDL receptor that has both genetic and clinical validation ( Petrilli et al, 2020 ). PCSK9 binds to the LDLR and is thought to reduce the recycling of these proteins from the cell surface (sending them to lysosomes instead), inhibiting LDL-particle removal from the extracellular fluid ( Deng et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association of Proprotein Convertase Subtilisin/Kexin Type 9 Plasma Levels in the ELSA-Brasil Study

et al. 2021

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Pharmacological inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) is an established therapeutic option to treat hypercholesterolemia, and plasma PCSK9 levels have been implicated in cardiovascular disease incidence. A number of genetic variants within the PCSK9 gene locus have been shown to modulate PCSK9 levels, but these only explain a very small percentage of the overall PCSK9 interindividual variation. Here we present data on the genetic association structure between PCSK9 levels and genom-wide genetic variation in a healthy sample from the general population. We performed a genome-wide association study of plasma PCSK9 levels in a sample of Brazilian individuals enrolled in the Estudo Longitudinal de Saude do Adulto cohort (n=810). Enrolled individuals were free from cardiovascular disease, diabetes and were not under lipid-lowering medication. Genome-wide genotyping was conducted using the Axiom_PMRA.r3 array, and imputation was performed using the TOPMED multi-ancestry sample panel as reference. Total PCSK9 plasma concentrations were determined using the Quantikine SPC900 ELISA kit. We observed two genome-wide significant loci and seven loci that reached the pre-defined value of p threshold of 1×10−6. Significant variants were near KCNA5 and KCNA1, and LINC00353. Genetic variation at the PCSK9 locus was able to explain approximately 4% of the overall interindividual variations in PCSK9 levels. Colocalization analysis using eQTL data suggested RWDD3, ATXN7L1, KCNA1, and FAM177A1 to be potential mediators of some of the observed associations. Our results suggest that PCSK9 levels may be modulated by trans genetic variation outside of the PCSK9 gene and this may have clinical implications. Understanding both environmental and genetic predictors of PCSK9 levels may help identify new targets for cardiovascular disease treatment and contribute to a better assessment of the benefits of long-term PCSK9 inhibition.

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Section: Discussionmentioning

confidence: 99%

Genome-Wide Association of Proprotein Convertase Subtilisin/Kexin Type 9 Plasma Levels in the ELSA-Brasil Study

et al. 2021

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“…As well as those outlined above, additional techniques have been used to study binary and ternary complex formation. These include dynamic scanning calorimetry, [43,53] size‐exclusion chromatography [16,23,54] microscale thermophoresis (MST), [55] native mass spectrometry, [56–58] and nuclear magnetic resonance (NMR) [51,59] . These techniques serve as orthogonal assays to the main strategies such as TR‐FRET and SPR, but they can also provide additional advantages.…”

Section: Biophysical Methods To Study Ternary Complex Formationmentioning

confidence: 99%

“…Ternary complex formation in intact cells can be studied using technologies such as NanoBRET [21,41,60–62] and NanoBiT, [54,63] as well as by cell imaging techniques (e. g. phase‐shift live cell imaging [64–65] ). Furthermore, other approaches, namely co‐immunoprecipitation, [66] chemo‐proteomics, [31] cellular thermal shift assay (CETSA), [48,53,67] in‐cell NMR, [68] and FP [69] can be used to address target engagement in lysates or in cells.…”

Section: Biophysical Methods To Study Ternary Complex Formationmentioning

confidence: 99%

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Biophysical and Computational Approaches to Study Ternary Complexes: A ‘Cooperative Relationship’ to Rationalize Targeted Protein Degradation

2023

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Degraders have illustrated that compound-induced proximity to E3 ubiquitin ligases can prompt the ubiquitination and degradation of disease-relevant proteins. Hence, this pharmacology is becoming a promising alternative and complement to available therapeutic interventions (e. g., inhibitors). Degraders rely on protein binding instead of inhibition and, hence, they hold the promise to broaden the druggable proteome. Biophysical and structural biology approaches have been the cornerstone of understanding and rationalizing degraderinduced ternary complex formation. Computational models have now started to harness the experimental data from these approaches with the aim to identify and rationally help design new degraders. This review outlines the current experimental and computational strategies used to study ternary complex formation and degradation and highlights the importance of effective crosstalk between these approaches in the advancement of the targeted protein degradation (TPD) field. As our understanding of the molecular features that govern druginduced interactions grows, faster optimizations and superior therapeutic innovations for TPD and other proximity-inducing modalities are sure to follow.

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Structure-activity relationship and biological evaluation of xanthine derivatives as PCSK9 inhibitors for the treatment of atherosclerosis

Qiao

Yang

et al. 2023

European Journal of Medicinal Chemistry

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From Screening to Targeted Degradation: Strategies for the Discovery and Optimization of Small Molecule Ligands for PCSK9

Cited by 4 publications

References 0 publications

Genome-Wide Association of Proprotein Convertase Subtilisin/Kexin Type 9 Plasma Levels in the ELSA-Brasil Study

Genome-Wide Association of Proprotein Convertase Subtilisin/Kexin Type 9 Plasma Levels in the ELSA-Brasil Study

Biophysical and Computational Approaches to Study Ternary Complexes: A ‘Cooperative Relationship’ to Rationalize Targeted Protein Degradation

Structure-activity relationship and biological evaluation of xanthine derivatives as PCSK9 inhibitors for the treatment of atherosclerosis

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