The signal peptide as a new target for drug design

Lumangtad, Liezel A.; Bell, Thomas W.

doi:10.1016/j.bmcl.2020.127115

Cited by 30 publications

(27 citation statements)

References 92 publications

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“…Perin et al (2016) showed that in the study of drug-based inhibition of hepatitis C virus (HCV) fusion peptide prevented the fusion of HCV to the cell membrane. It is known that signal peptides play an important role in the translocation of viral and bacterial proteins into host cells (Garcia et al 1988, Ignatova et al 2002, Lumangtad & Bell 2020, Vermeire et al 2014. A study by showed that the signal peptide can contribute to the severity of infection through viral protein translocation.…”

Section: Discussionmentioning

confidence: 99%

SARS CoV-2 SPIKE GLYCOPROTEIN MUTATIONS AND CHANGES IN PROTEIN STRUCTURE

Akbulut

2021

Trakya University Journal of Natural Sciences

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Severe Acute Respiratory Syndrome Corona Virus-2 (SARS CoV-2) is a single-stranded positive polarity RNA virus with a high virulence effect. Spike (S) glycoprotein is the outermost component of the SARS CoV-2 virion and is important in the entry of the virus into the cell via the angiotensin converting enzyme 2 (ACE2) receptor. ACE2 plays an important role in the regulation of human blood pressure by converting the vasoconstrictor angiotensin 2 to the vasodilator angiotensin 1-7. In this study, the changes that mutations in Asian isolates may cause in S glycoprotein structure were analyzed and modeled to contribute to drug and vaccine targeting studies. Genome, proteome and mutation analyses were done using bioinformatics tools (MAFFT, MegaX, PSIPRED, MolProbity, PyMoL). Protein modelling was performed using ProMod3. We detected 26 mutations in the S glycoprotein. The changes that these mutations reveal in the general topological and conformational structure of the S glycoprotein may affect the virulence features of SARS CoV-2. It was determined that mutations converted the receptor binding domain (RBD) from down-formation to like-up formation. It is thought that conformational change occurring after mutation in RBD may cause an increase in receptor affinity. These findings could be beneficial for disease prevention of and drug/vaccine development for SARS CoV-2. Özet: Şiddetli akut solunum yolu sendromu koronavirüsü-2 (SARS CoV-2) yüksek virülans etkiye sahip tek zincirli pozitif polariteli RNA virüsüdür. Spike (S) glikoprotein SARS CoV-2 virionunun en dıştaki bileşenidir ve anjiyotensin dönüştürücü enzim 2 (ACE2) reseptörü aracılığı ile virüsün hücreye girişinde önemlidir. ACE2, vazokonstriktör anjiyotensin 2'yi vazodilatör anjiyotensin 1-7'ye dönüştürerek insanda kan basıncının düzenlenmesinde önemli roller üstlenir. Bu çalışmada, Asya izolatlarındaki mutasyonların S glikoprotein yapısında neden olabileceği değişiklikler analiz edilmiş ve ilaç ve aşı hedefleme çalışmalarına katkıda bulunmak üzere modellenmiştir. Genom, proteom ve mutasyon analizleri biyoinformatik araçları (MAFFT, MegaX, PSIPRED, MolProbity, PyMoL) kullanılarak yapıldı. Protein modellemesi ProMod3 kullanılarak yapıldı. S glikoproteinde 26 mutasyon tespit edilmiştir. Bu mutasyonların S glikoproteininin genel topolojik ve konformasyonel yapısında ortaya çıkardığı değişiklikler, SARS CoV-2'nin virülans özelliklerini etkileyebilir. Mutasyonların reseptör bağlanma bölgesini (RBB) kapalı formasyondan açık formasyon benzeri bir yapıya dönüştürdüğü belirlenmiştir. RBB'de mutasyondan sonra meydana gelen konformasyonel değişimin reseptör afinitesinde bir artışa neden olabileceği düşünülmektedir. Bu bulgular hastalığın önlenmesi ve SARS CoV-2 ilaç ve aşı geliştirme çalışmaları için faydalı olabilir.

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Section: Discussionmentioning

confidence: 99%

SARS CoV-2 SPIKE GLYCOPROTEIN MUTATIONS AND CHANGES IN PROTEIN STRUCTURE

Akbulut

2021

Trakya University Journal of Natural Sciences

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“…[9] have determined the features that define ER signal peptides as Sec62‐/Sec63‐dependent and provided a compelling case that these components assist in the gating of the Sec61 translocon. Their work has expanded our current view of Sec61‐mediated cotranslational translocation and raised new questions about the precise mechanistic contributions of ER signal peptide diversity [2,6], a rapidly emerging and potentially druggable target for the treatment of numerous diseases [16].…”

Section: Discussionmentioning

confidence: 99%

Membrane translocation at the ER: with a little help from my friends

O’Keefe

High

2020

The FEBS Journal

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The Sec61 complex is the proteinaceous pore through which one-third of mammalian polypeptides access the lumen of the endoplasmic reticulum (ER) during their translocation across, or insertion into, the ER membrane. N-terminal ER signal peptides mediate polypeptide targeting to, and opening of, the Sec61 channel in a substrate-specific manner. Here, we discuss the recently defined features of ER signal peptides which necessitate the use of the accessory components Sec62 and Sec63 during the Sec61-mediated cotranslational translocation of newly synthesized secretory proteins.

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“…Unlike the small proteins that cross the ER membrane, newly synthesized ACE2 is targeted to the translocon (ER membrane channel) via its 17 amino acid N-terminal signal sequence. As translation proceeds, ACE2 binds to the channel and passes to the ER membrane where the ribosome is dissociated [64]. Once ACE2 is well folded and N-glycosylated in the ER, it exits through transport vesicles and enters the Golgi apparatus through its cis face.…”

Section: Subcellular Localization and Intracellular Trafficking Of Ace2mentioning

confidence: 99%

ACE2 Nascence, Trafficking and SARS-CoV-2 Pathogenesis: The Saga Continues

Badawi

Ali

2020

Preprint

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With the emergence of the novel corona virus SARS-CoV-2 since December 2019, more than 43 million cases have been reported worldwide. This virus has shown high infectivity and severe symptoms in some cases leading to over 1 million deaths globally. Despite the collaborative and concerted research efforts that has been made, no effective treatment for COVID-19 (corona virus disease-2019) is currently available. SARS-CoV-2 uses the angiotensin converting enzyme 2 (ACE2) as an initial mediator for viral attachment and host cell invasion. ACE2 is widely distributed in human tissues including the cell surface of lung cells which represent the primary site of the infection. Inhibiting or reducing cell surface availability of ACE2 represents a promising therapy for tackling COVID-19. In this context, most ACE2–based therapeutic strategies have aimed to achieve this through the use of angiotensin converting enzyme (ACE) inhibitors or neutralizing the virus by exogenous administration of ACE2. However, through this review, we present another perspective focusing on the subcellular localization and trafficking of ACE2. Membrane targeting of ACE2, shedding and its cellular trafficking pathways including internalization are not well elucidated. Therefore, hereby we present an overview on the fate of newly synthesized ACE2, its post translational modifications, what is known of its trafficking pathways. In addition, we highlight the possibility that some of the identified ACE2 missense variants might affect its trafficking efficiency and localization and hence may explain some of the observed variable severity of SARS-CoV-2 infections. Extensive understanding of these processes is necessary to evaluate the potential use of ACE2 as a credible therapeutic target.

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The signal peptide as a new target for drug design

Cited by 30 publications

References 92 publications

SARS CoV-2 SPIKE GLYCOPROTEIN MUTATIONS AND CHANGES IN PROTEIN STRUCTURE

SARS CoV-2 SPIKE GLYCOPROTEIN MUTATIONS AND CHANGES IN PROTEIN STRUCTURE

Membrane translocation at the ER: with a little help from my friends

ACE2 Nascence, Trafficking and SARS-CoV-2 Pathogenesis: The Saga Continues

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