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

Abstract

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.

Virtual Screening-Based Peptides Targeting Spike Protein to Inhibit Porcine Epidemic Diarrhea Virus (PEDV) Infection

“…However, it has been reported that nAbs, targeting RBD and NTD of SARS-CoV-2 S protein in the S1 subunit, which its inhibitory effect is not constant. The main reason that lies in RBD and NTD region of SARS-CoV-2 S protein is more easily to be mutational frequency than other components of the S protein [ 38 ]. In other words, neutralizing antibody inhibitors designed for the RBD and NTD regions of SARS-CoV-2 S protein make it difficult to generate immunogenicity and protect against other human coronaviruses [ 39 ].…”

Bioinformatic analysis of the S protein of human respiratory coronavirus

“…This class of drugs currently targets mainly N proteins, based on their structural conservation. In contrast, antibodies are still more often developed against S proteins ( Bai et al, 2021 , Lan et al, 2022 , Mohammed, 2022 ; Su et al, n.d.). We predicted the epitopes of human respiratory coronavirus S proteins using Predict Antigenic Peptides, and we found 61 epitopes for SARS ShanghaiQXC2 S protein, 60 epitopes for MERS nasal swab S protein, 55 epitopes for HCoV-HKU1 SI17244 S protein, and 63 epitopes for SARS -CoV-2 Wuhan-Hu-1 S protein.…”

“…However, the mechanism of host invasion by HCoV HKU1 is not yet clear ( Raj et al, 2013 , Yang et al, 2014 ). The mechanism of binding between the coronavirus S protein and its receptor has been studied in depth and has led to the development of several therapeutic or blocking drugs ( Lan et al, 2022 , Totura and Bavari, 2019 ).…”

SARS‐CoV‐2 Omicron XBB subvariants exhibit enhanced fusogenicity and substantial immune evasion in elderly population, but high sensitivity to pan‐coronavirus fusion inhibitors

“…All S genes are from GIASID, including WT‐D614G (EPI_ISL_412912), BA.1 (EPI_ISL_7357684), BA.2 (EPI_ISL_9022266), BA.2.12.1 (EPI_ISL_16342984), BA.2.75 (EPI_ISL_13583747), BA.5.2 (EPI_ISL_12278976), BA4.6 (EPI_ISL_16344583), BF.7 (EPI_ISL_16997169), XBB (EPI_ISL_15766671), and XBB.1.5 (EPI_ISL_16346200). The sequences of EK1 and EK1C4, as previously described, 15–17 were “SLDQINVTFLDLEYEMKKLEEAIKKLEESYIDLKEL” and “SLDQINVTFLDLEYEMKKLEEAIKKLEESYIDLKEL‐GSGSG‐PEG4‐C(chol),” respectively.…”

“…The sequences of EK1 and EK1C4, as previously described, [15][16][17] were "SLDQINVTFLDLEYEMKKLEEAIKKLEESYIDLKEL" and "SLDQINVTFLD LEYEMKKLEEAIKKLEESYIDLKEL-GSGSG-PEG4-C(chol)," respectively.…”