A novel cyclic γ-AApeptide-based long-acting pan-coronavirus fusion inhibitor with potential oral bioavailability by targeting two sites in spike protein

Xue, Shuai; Wang, Xinling; Wang, Lei; Xu, Wei; Xia, Shuai; Sun, Lujia; Wang, Shaohui; Shen, Ning; Yang, Ziyin; Huang, Bo; Li, Sihao; Cao, Chuanhai; Calcul, Laurent; Sun, Xingmin; Lu, Lu; Cai, Jianfeng; Jiang, Shibo

doi:10.1038/s41421-022-00455-6

Cited by 15 publications

(24 citation statements)

References 47 publications

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“…Most recently, we have identified a cyclic peptidomimetic, S-20-1, through screening of a one-bead-two-compound (OBTC) cyclic γ-AApeptide library and modification of the compound. 43 We found that S-20-1 effectively inhibited infection of SARS-CoV-2 and its variants,…”

Section: Cyclic Peptidomimetic-based Fusion Inhibitors With Potential...mentioning

confidence: 75%

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Pan‐coronavirus fusion inhibitors to combat COVID‐19 and other emerging coronavirus infectious diseases

Lan

Wang

Jiao

et al. 2022

Journal of Medical Virology

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Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the causative agent of the currently ongoing coronavirus disease 2019 (COVID‐19) pandemic, has posed a serious threat to global public health. Recently, several SARS‐CoV‐2 variants of concern (VOCs) have emerged and caused numerous cases of reinfection in convalescent COVID‐19 patients, as well as breakthrough infections in vaccinated individuals. This calls for the development of broad‐spectrum antiviral drugs to combat SARS‐CoV‐2 and its VOCs. Pan‐coronavirus fusion inhibitors, targeting the conserved heptad repeat 1 (HR1) in spike protein S2 subunit, can broadly and potently inhibit infection of SARS‐CoV‐2 and its variants, as well as other human coronaviruses. In this review, we summarized the most recent development of pan‐coronavirus fusion inhibitors, such as EK1, EK1C4, and EKL1C, and highlighted their potential application in combating current COVID‐19 infection and reinfection, as well as future emerging coronavirus infectious diseases.

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Section: Cyclic Peptidomimetic-based Fusion Inhibitors With Potential...mentioning

confidence: 75%

“…Therefore, S‐20‐1 has potential for further development as an orally applied therapeutic and prophylactic against SARS‐CoV‐2 and other emerging and reemerging HCoVs. 43 …”

Section: Development Of Pan‐cov Fusion Inhibitorsmentioning

confidence: 99%

Pan‐coronavirus fusion inhibitors to combat COVID‐19 and other emerging coronavirus infectious diseases

Lan

Wang

Jiao

et al. 2022

Journal of Medical Virology

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“…Most recently, however, we have identified a novel cyclic γ-AApeptide, S-20-1, which has potent fusion inhibitory activity against SARS-CoV-2 and its variants, as well as MERS-CoV, SARS-CoV, HCoV-OC43, HCoV-229E, and HCoV-NL63. It also exhibits long half-life (t 1/2 : 24h) and potential oral bioavailability by targeting SARS-CoV-2 HR1 in S2 subunit and RBD in S1 subunit [ 27 ]. At the same time, we have designed and engineered an HR2-targeting recombinant protein, 5-Helix, which consists of 3 HR1 and 2HR2 fragments.…”

Section: Resultsmentioning

confidence: 99%

“…HIV-1 backbone-based Pseudovirus (PsV) bearing wild or mutant SARS-CoV2 S protein was produced, as previously described [ 27 ]. Caco2 cells were used as target cells and were seeded in wells of a 96-well plate 48 h in advance.…”

Section: Methodsmentioning

confidence: 99%

SARS-CoV-2 Omicron subvariants exhibit distinct fusogenicity, but similar sensitivity, to pan-CoV fusion inhibitors

Xia

Wang

Jiao

et al. 2023

Emerging Microbes & Infections

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Continuous emergence of the Omicron variant, along with its subvariants, has caused an increasing number of infections, reinfections, and vaccine-breakthrough infections, seriously threatening human health. Recently, several new Omicron subvariants, such as BA.5, BA.2.75, BA.4.6, and BF.7, bearing distinct mutation profiles in their spike (S) proteins, have significantly increased their capacity to evade vaccine-induced immunity and have shown enhanced infectivity and transmissibility, quickly becoming dominant sublineages. In this study, we found the S proteins of these Omicron subvariants to have 2- to 4-fold more efficient membrane fusion kinetics than that of the original Omicron variant (BA.1), indicating that these novel Omicron subvariants might possess increased pathogenicity. We also identified that peptide-based pan-CoV fusion inhibitors, EK1 and EK1C4, showed equal efficacy against membrane fusion mediated by S proteins of the noted Omicron subvariants and infection by their pseudoviruses. Additionally, either immune sera induced by wild-type (WT) SARS-CoV-2 RBD-based vaccine or BA.2 convalescent sera showed potent synergism with EK1 against both WT SARS-CoV-2 and various Omicron subvariants, further suggesting that EK1-based fusion inhibitors are promising candidates for development as clinical antiviral agents against the currently circulating Omicron subvariants.

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“…6 ). 137 , 138 In human ACE2, Lys-31 and Lys-353 are sensitive to the RBD. 139 Its glycosylation sites Asn-90 and Asn-322 also demonstrated the ability to interfere with S protein binding in a recent study.…”

Section: Covid-19 Therapeutic Targets For Small Moleculesmentioning

confidence: 99%

Small molecules in the treatment of COVID-19

Lei

Chen

Jin

et al. 2022

Sig Transduct Target Ther

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The outbreak of COVID-19 has become a global crisis, and brought severe disruptions to societies and economies. Until now, effective therapeutics against COVID-19 are in high demand. Along with our improved understanding of the structure, function, and pathogenic process of SARS-CoV-2, many small molecules with potential anti-COVID-19 effects have been developed. So far, several antiviral strategies were explored. Besides directly inhibition of viral proteins such as RdRp and Mpro, interference of host enzymes including ACE2 and proteases, and blocking relevant immunoregulatory pathways represented by JAK/STAT, BTK, NF-κB, and NLRP3 pathways, are regarded feasible in drug development. The development of small molecules to treat COVID-19 has been achieved by several strategies, including computer-aided lead compound design and screening, natural product discovery, drug repurposing, and combination therapy. Several small molecules representative by remdesivir and paxlovid have been proved or authorized emergency use in many countries. And many candidates have entered clinical-trial stage. Nevertheless, due to the epidemiological features and variability issues of SARS-CoV-2, it is necessary to continue exploring novel strategies against COVID-19. This review discusses the current findings in the development of small molecules for COVID-19 treatment. Moreover, their detailed mechanism of action, chemical structures, and preclinical and clinical efficacies are discussed.

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A novel cyclic γ-AApeptide-based long-acting pan-coronavirus fusion inhibitor with potential oral bioavailability by targeting two sites in spike protein

Cited by 15 publications

References 47 publications

Pan‐coronavirus fusion inhibitors to combat COVID‐19 and other emerging coronavirus infectious diseases

Pan‐coronavirus fusion inhibitors to combat COVID‐19 and other emerging coronavirus infectious diseases

SARS-CoV-2 Omicron subvariants exhibit distinct fusogenicity, but similar sensitivity, to pan-CoV fusion inhibitors

Small molecules in the treatment of COVID-19

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