Cooperative and structural relationships of the trimeric Spike with infectivity and antibody escape of the strains Delta (B.1.617.2) and Omicron (BA.2, BA.5, and BQ.1)

de Souza, Anacleto Silva; de Souza, Robson Francisco; Guzzo, Cristiane Rodrigues

doi:10.1007/s10822-023-00534-0

Cited by 3 publications

(2 citation statements)

References 115 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since the virus's emergence, until March 2024, more than 3,9 thousand different genomes have been recorded [6]. The virus accesses the host cell through the Spike protein, which binds to the human ACE2 receptor [5,[7][8][9]. The virus may infect the human cells bys two primary entry pathways: (1) Fusion of the virus membrane with the cell membrane, facilitating the release of its genetic material into the cytoplasm of the host cell or/and (2) Internalization of the virus via endocytosis.…”

Section: Introductionmentioning

confidence: 99%

3-Chymotrypsin-like Protease (3CLpro): Validation as a Molecular Target, Proposal of a Novel Catalytic Mechanism, and Inhibitors in Preclinical and Clinical Trials

Amorim,

Soares,

Ferrari

et al. 2024

Preprint

View full text Add to dashboard Cite

Proteases represent common targets in combating infectious diseases including COVID-19. The 3-chymotrypsin-like protease (3CLpro) is a validated molecular target for COVID-19 and it is key for developing potent and selective inhibitors for inhibiting viral replication of SARS-CoV-2. In this review, we discuss structural relationships and diverse subsites of 3CLpro, shedding light on the pivotal role of dimerization and active site architecture in substrate recognition and catalysis. Our analysis of bioinformatics and other published studies unveil a proposal of a novel catalytic mechanism for the SARS-CoV-2 polyprotein cleavage by 3CLpro, centering on the triad mechanism involving His41-Cys145-Asp187 and its indispensable role in viral replication. Recognizing Asp187 as a crucial component in the catalytic process underscores its significance as a fundamental pharmacophoric element in drug design. Next, we provide an overview of both covalent and non-covalent inhibitors, elucidating advancements in drug development observed in preclinical and clinical trials. By highlighting various chemical classes and their pharmacokinetic profiles, our review aims to guide future research directions toward the development of highly selective inhibitors, underscore the significance of 3CLpro as a validated therapeutic target, and propel the progression of drug candidates through preclinical and clinical phases.

show abstract

Section: Introductionmentioning

confidence: 99%

3-Chymotrypsin-like Protease (3CLpro): Validation as a Molecular Target, Proposal of a Novel Catalytic Mechanism, and Inhibitors in Preclinical and Clinical Trials

Amorim,

Soares,

Ferrari

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Since the virus’s emergence, until March 2024, more than 3.9 thousand different genomes have been recorded [ 7 ]. The virus accesses the host cell through the Spike protein, which binds to the human ACE2 receptor [ 6 , 8 , 9 , 10 ]. The virus may infect human cells by two primary entry pathways: (1) fusion of the virus membrane with the cell membrane, facilitating the release of its genetic material into the cytoplasm of the host cell or/and (2) internalization of the virus via endocytosis.…”

Section: Introductionmentioning

confidence: 99%

3-Chymotrypsin-like Protease (3CLpro) of SARS-CoV-2: Validation as a Molecular Target, Proposal of a Novel Catalytic Mechanism, and Inhibitors in Preclinical and Clinical Trials

Amorim,

Soares,

Ferrari

et al. 2024

Viruses

Self Cite

View full text Add to dashboard Cite

Proteases represent common targets in combating infectious diseases, including COVID-19. The 3-chymotrypsin-like protease (3CLpro) is a validated molecular target for COVID-19, and it is key for developing potent and selective inhibitors for inhibiting viral replication of SARS-CoV-2. In this review, we discuss structural relationships and diverse subsites of 3CLpro, shedding light on the pivotal role of dimerization and active site architecture in substrate recognition and catalysis. Our analysis of bioinformatics and other published studies motivated us to investigate a novel catalytic mechanism for the SARS-CoV-2 polyprotein cleavage by 3CLpro, centering on the triad mechanism involving His41-Cys145-Asp187 and its indispensable role in viral replication. Our hypothesis is that Asp187 may participate in modulating the pKa of the His41, in which catalytic histidine may act as an acid and/or a base in the catalytic mechanism. Recognizing Asp187 as a crucial component in the catalytic process underscores its significance as a fundamental pharmacophoric element in drug design. Next, we provide an overview of both covalent and non-covalent inhibitors, elucidating advancements in drug development observed in preclinical and clinical trials. By highlighting various chemical classes and their pharmacokinetic profiles, our review aims to guide future research directions toward the development of highly selective inhibitors, underscore the significance of 3CLpro as a validated therapeutic target, and propel the progression of drug candidates through preclinical and clinical phases.

show abstract

Temperature-dependent Spike-ACE2 interaction of Omicron subvariants is associated with viral transmission

Benlarbi,

Ding,

Bélanger

et al. 2024

mBio

View full text Add to dashboard Cite

The continued evolution of severe acute respiratory syndrome 2 (SARS-CoV-2) requires persistent monitoring of its subvariants. Omicron subvariants are responsible for the vast majority of SARS-CoV-2 infections worldwide, with XBB and BA.2.86 sublineages representing more than 90% of circulating strains as of January 2024. To better understand parameters involved in viral transmission, we characterized the functional properties of Spike glycoproteins from BA.2.75, CH.1.1, DV.7.1, BA.4/5, BQ.1.1, XBB, XBB.1, XBB.1.16, XBB.1.5, FD.1.1, EG.5.1, HK.3, BA.2.86 and JN.1. We tested their capacity to evade plasma-mediated recognition and neutralization, binding to angiotensin-converting enzyme 2 (ACE2), their susceptibility to cold inactivation, Spike processing, as well as the impact of temperature on Spike-ACE2 interaction. We found that compared to the early wild-type (D614G) strain, most Omicron subvariants' Spike glycoproteins evolved to escape recognition and neutralization by plasma from individuals who received a fifth dose of bivalent (BA.1 or BA.4/5) mRNA vaccine and improve ACE2 binding, particularly at low temperatures. Moreover, BA.2.86 had the best affinity for ACE2 at all temperatures tested. We found that Omicron subvariants’ Spike processing is associated with their susceptibility to cold inactivation. Intriguingly, we found that Spike-ACE2 binding at low temperature was significantly associated with growth rates of Omicron subvariants in humans. Overall, we report that Spikes from newly emerged Omicron subvariants are relatively more stable and resistant to plasma-mediated neutralization, present improved affinity for ACE2 which is associated, particularly at low temperatures, with their growth rates. IMPORTANCE The persistent evolution of SARS-CoV-2 gave rise to a wide range of variants harboring new mutations in their Spike glycoproteins. Several factors have been associated with viral transmission and fitness such as plasma-neutralization escape and ACE2 interaction. To better understand whether additional factors could be of importance in SARS-CoV-2 variants’ transmission, we characterize the functional properties of Spike glycoproteins from several Omicron subvariants. We found that the Spike glycoprotein of Omicron subvariants presents an improved escape from plasma-mediated recognition and neutralization, Spike processing, and ACE2 binding which was further improved at low temperature. Intriguingly, Spike-ACE2 interaction at low temperature is strongly associated with viral growth rate, as such, low temperatures could represent another parameter affecting viral transmission.

show abstract

Cooperative and structural relationships of the trimeric Spike with infectivity and antibody escape of the strains Delta (B.1.617.2) and Omicron (BA.2, BA.5, and BQ.1)

Cited by 3 publications

References 115 publications

3-Chymotrypsin-like Protease (3CLpro): Validation as a Molecular Target, Proposal of a Novel Catalytic Mechanism, and Inhibitors in Preclinical and Clinical Trials

3-Chymotrypsin-like Protease (3CLpro): Validation as a Molecular Target, Proposal of a Novel Catalytic Mechanism, and Inhibitors in Preclinical and Clinical Trials

3-Chymotrypsin-like Protease (3CLpro) of SARS-CoV-2: Validation as a Molecular Target, Proposal of a Novel Catalytic Mechanism, and Inhibitors in Preclinical and Clinical Trials

Temperature-dependent Spike-ACE2 interaction of Omicron subvariants is associated with viral transmission

Contact Info

Product

Resources

About