Homo-PROTAC mediated suicide of MDM2 to treat non-small cell lung cancer

He, Shipeng; Ma, Junhui; Fang, Yuxin; Liu, Ying; Wu, Shanchao; Dong, Guoqiang; Wang, Wei; Sheng, Chunquan

doi:10.1016/j.apsb.2020.11.022

Cited by 62 publications

(82 citation statements)

References 43 publications

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“…Lopinavir had a similar binding position as remdesivir, it formed a hydrogen bond with Val 330 but alkyl and, Pi-alkyl interaction with Val 398, TYR 273, ALA 379, ALA 383, ALA 382, PHE 396 (see Figure S3). Wu et al ( 2020 ) as well reported the inhibitory potential of remdesivir, according to the study; it binds to the bottom RNA template channel, a position that is for the acceptor template nucleotide.…”

Section: Resultsmentioning

confidence: 95%

“…Although remdesivir as an ATP analog is a potent inhibitor of RNA-dependent RNA polymerases (RdRps). It can terminate RNA synthesis by replacing ATP during polymerization and thus known as chain terminator drug (Wu et al 2020 ). Lopinavir had a similar binding position as remdesivir, it formed a hydrogen bond with Val 330 but alkyl and, Pi-alkyl interaction with Val 398, TYR 273, ALA 379, ALA 383, ALA 382, PHE 396 (see Figure S3).…”

Section: Resultsmentioning

confidence: 99%

“…The genomic structure of the virus is a 5'-leader-UTR replicase-S(Spike)-E(Envelop)-M(Membrane)-N(Nucleocapsid)-3'ÚTR poly (A) tail, with the accessory genes responsible for viral pathogenesis interspersed within the structural genes at the 3' end of the genome (Fehr and Perlman 2015 ; Zhao et al 2012 ). The spike protein is the point of attachment to the Angiotensin Converting Enzyme (ACE) receptor and it mobilizes the subsequent entry into host cells (Wu et al 2020 ). The M and E proteins on the other hand function in the viral assembly while the N protein is responsible for viral RNA synthesis (Fehr and Perlman 2015 ; Song et al 2019 ).…”

Section: Introductionmentioning

confidence: 99%

“…The M and E proteins on the other hand function in the viral assembly while the N protein is responsible for viral RNA synthesis (Fehr and Perlman 2015 ; Song et al 2019 ). With the knowledge of the viral genomic structure and the behavior in the human host, studies on drug development could focus on the design of therapies that could either be targeted to act on the host cells or directly on the virus itself (Wu et al 2020 ). For instance, therapies could be targeted to block the pathways of human cells required for viral entry/or replication (Agrawal et al 2015 ; Han et al 2006 ; Li et al 2003 ) or prevent viral replication through inhibition of critical viral enzymes (3-chymotrypsin like protease or papain-like proteases).…”

Section: Introductionmentioning

confidence: 99%

“…For instance, therapies could be targeted to block the pathways of human cells required for viral entry/or replication (Agrawal et al 2015 ; Han et al 2006 ; Li et al 2003 ) or prevent viral replication through inhibition of critical viral enzymes (3-chymotrypsin like protease or papain-like proteases). Furthermore, inhibition of viral RNA synthesis (Inhibition of RNA dependent RNA polymerase and Helicase) and/or block the binding to host cells and self-assembly process (Wu et al 2020 ). Strategy in the current fight against coronavirus involves testing existing broad-spectrum of already approved and trial drugs.…”

Section: Introductionmentioning

confidence: 99%

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In silico studies of Potency and safety assessment of selected trial drugs for the treatment of COVID-19

Adegbola

Fadahunsi

Adegbola

et al. 2021

In Silico Pharmacol.

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SARS-CoV-2 has caused millions of infections and hundreds of thousands of deaths globally. Presently, no cure for SARS-CoV-2 infection is available; thus, all hands are on deck for new drug discovery. Although, several studies have reported the potentials of some already approved drugs for the treatment of COVID-19. This study attempted to compare the potency and safety of some these trial drugs via in silico methods. The binding affinity and interactions of the trial drugs with proteins involved in viral polyprotein processing (Papain like protease (PLpro) and Chymotrypsin like-protease (3-CLpro), viral replication (RNA dependent RNA polymerase (RdRp)) and host protease were studied in this work. The pharmacokinetic properties and toxicity potentials of the trial drugs were also predicted using vNN Web Server for ADMET Predictions. From the results, Merimepodib and Dexamethaxone demonstrated the most significant inhibitory potential against the PLpro. The binding affinity (∆G°) for merimepodib was − 7.2 kcal/mol while the inhibition constant was 6.3 µM. The binding affinity of the inhibitors for CLpro ranged from − 5.6 to − 9.5 kcal/mol. whereas Lopinavir (− 7.7 kcal/mol) exhibited the strongest affinity for RdRp. Overall, our results showed that all the ligands have a higher affinity for the 3-Chymotrypsin like protease than the other proteins (PLpro, RdRp, and Host protease). Among these compounds lopinavir, merimepodib and dexamethasone could be inhibitors with potentials for the treatment of SARS-CoV-2. However, the only dexamethasone has attractive pharmacokinetic and toxicity properties probable for drug development; therefore, our study provides a basis for developing effective drugs targeting a specific protein in the SARS-CoV-2 life cycle. Supplementary Information The online version contains supplementary material available at 10.1007/s40203-021-00105-x.

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Section: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

In silico studies of Potency and safety assessment of selected trial drugs for the treatment of COVID-19

Adegbola

Fadahunsi

Adegbola

et al. 2021

In Silico Pharmacol.

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PROTAC Degraders

Ciulli

Hsia

2022

Protein Homeostasis in Drug Discovery

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Folate‐PEG‐PROTAC Micelles for Enhancing Tumor‐Specific Targeting Proteolysis In Vivo

Ma,

Fang,

Sun

et al. 2024

Adv Healthcare Materials

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Proteolysis targeting chimeras (PROTACs) technology has been rapidly developed as a novel and selective medicinal strategy for the degradation of cellular proteins in cancer therapy. However, the applications of PROTACs as the heterobifunctional molecules are largely limited by high molecular weight, low bioavailability, poor permeability, insufficient targeting and low efficacy in vivo. Herein, self‐assembling micelles of FA‐PEG‐PROTAC are designed for cancer cell selective targeting and reductive‐response proteolysis in tumor‐bearing mice. FA‐PEG‐PROTAC are prepared by conjugating folic acid (FA)‐PEG with EGFR‐targeting PROTAC (PRO) via a disulfide bond. The FA‐PEG‐PROTAC micelles, formed by self‐assembling, is demonstrated to significantly improve tumor targeting efficacy and exhibit excellent anti‐tumor efficacy in mouse xenograft model compared to the traditional PROTACs. The strategy of applying self‐assembled FA‐PEG‐PROTAC micelles in tumor therapy can not only improve targeted proteolysis efficiency but broaden applications in the development of PROTAC‐based drugs.This article is protected by copyright. All rights reserved

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Homo-PROTAC mediated suicide of MDM2 to treat non-small cell lung cancer

Cited by 62 publications

References 43 publications

In silico studies of Potency and safety assessment of selected trial drugs for the treatment of COVID-19

In silico studies of Potency and safety assessment of selected trial drugs for the treatment of COVID-19

PROTAC Degraders

Folate‐PEG‐PROTAC Micelles for Enhancing Tumor‐Specific Targeting Proteolysis In Vivo

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