Discovery of Small Anti‐ACE2 Peptides to Inhibit SARS‐CoV‐2 Infectivity

Abstract

COVID‐19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), which infects host cells by binding its viral spike protein receptor‐binding domain (RBD) to the angiotensin converting enzyme 2 (ACE2) on host cells. Blocking the SARS‐CoV‐2‐RBD/ACE2 interaction is, therefore, a potential strategy to inhibit viral infections. Using a novel biopanning strategy, a small anti‐ACE2 peptide is discovered, which shows high affinity and specificity to human ACE2. It blocks not only the SARS‐CoV‐2‐RBD/ACE2 interaction but also the SARS‐CoV‐1‐RBD/ACE2 interaction. Moreover, it inhibits SARS‐CoV‐2 infection in Vero‐E6 cells. The peptide shows negligible cytotoxicity in Vero‐E6 cells and Huh7 cells. In vivo short‐term lung toxicity study also demonstrates a good safety of the peptide after intratracheal administration. The anti‐ACE2 peptide can be potentially used as a prophylactic or therapeutic agent for SARS‐CoV‐2 or other ACE2‐mediated viruses. The strategy used in this study also provides a fast‐track platform to discover other antiviral peptides, which will prepare the world for future pandemics.

SARS-CoV-2 pan-variant inhibitory peptides deter S1-ACE2 interaction and neutralize delta and omicron pseudoviruses

“… [1] , [2] , [3] , [4] , [5] , [6] , [7] , [8] , [9] , [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] , [55] , [56] , [57] , [58] , [59] , [60] , [61] , [62] , [63] , [64] , [65] , [66] , [67] , [68] , [69] , [70] , [71] , [72] ...…”

Computational Design of Miniproteins as SARS-CoV-2 Therapeutic Inhibitors

“…Smaller size proteins have several advantages as in reduced production costs with high output, low side effects, high selectivity, etc. [ 35 , 36 ]. Cao et al identified LCB1 as a smaller miniprotein with 56 AAs [ 20 ], but it is still considered to be a large inhibitor [ 25 ].…”

“…A series of concentrations of each miniprotein (0.1, 1, 10, 50, 100, 200, 500, and 1000 nM) will be analyzed to calculate the equilibrium dissociation constant (K D ) values. Next, we will select the miniproteins that exhibit high affinity to SARS-CoV-2 RBD and study whether they can block the SARS-CoV-2 RBD/ACE2 interaction as we reported [ 35 ]. A 96-well plate will be coated with SARS-CoV-2 RBD protein, blocked with bovine serum albumin (BSA), and incubated with the miniproteins at room temperature for 1 h. After washing, biotinylated-ACE2 protein will be added to the wells and incubated for 1 h. Streptavidin-HRP and substrate will be finally added to measure absorbance at 450 nm.…”

“…One main advantage of MP3 is its small size, which results in lower production costs and high yield. This smaller size may also lead to high selectivity binding to a target and low interference with biological processes, thus reducing its side effects [ 25 , 35 ]. The structure of the last step in M3-MD is used to generate M3-DFT which has all 40 AAs of MP3, a similar segment of 108 AAs in RBD, and 3 Na + ions.…”

Will Peptides Help to Stop COVID-19?

“…It was reported that many out of 26 analyzed peptides signifi cantly aff ected the biological activity of the recombinant human ACE2. However, the peptide CPS4 (NNYLWWMTEYHD) and its dimer eff ectively blocked virus entry into the cell, but did not aff ect the functional activity of ACE2 [93]. It should be mentioned that no results on the in vivo activity have been reported for any of the discussed peptides (Table 2).…”