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Review
. 2024 Jan 30;3(1):100145.
doi: 10.1016/j.cellin.2023.100145. eCollection 2024 Feb.

ACE2-using merbecoviruses: Further evidence of convergent evolution of ACE2 recognition by NeoCoV and other MERS-CoV related viruses

Qing Xiong  1 , Chengbao Ma  1 , Chen Liu  1 , Fei Tong  1 , Meiling Huang  1 , Huan Yan  1
Affiliations
Review

ACE2-using merbecoviruses: Further evidence of convergent evolution of ACE2 recognition by NeoCoV and other MERS-CoV related viruses

Qing Xiong et al. Cell Insight. .

Abstract

Angiotensin-converting enzyme 2 (ACE2) was recognized as an entry receptor shared by coronaviruses from Sarbecovirus and Setracovirus subgenera, including three human coronaviruses: SARS-CoV, SARS-CoV-2, and NL63. We recently disclosed that NeoCoV and three other merbecoviruses (PDF-2180, MOW15-22, PnNL 2018B), which are MERS-CoV relatives found in African and European bats, also utilize ACE2 as their functional receptors through unique receptor binding mechanisms. This unexpected receptor usage assumes significance, particularly in light of the prior recognition of Dipeptidyl peptidase-4 (DPP4) as the only known protein receptor for merbecoviruses. In contrast to other ACE2-using coronaviruses, NeoCoV and PDF-2180 engage a distinct and relatively compact binding surface on ACE2, facilitated by protein-glycan interactions, which is demonstrated by the Cryo-EM structures of the receptor binding domains (RBDs) of these viruses in complex with a bat ACE2 orthologue. These findings further support the hypothesis that phylogenetically distant coronaviruses, characterized by distinct RBD structures, can independently evolve to acquire ACE2 affinity during inter-species transmission and adaptive evolution. To date, these viruses have exhibited limited efficiency in entering human cells, although single mutations like T510F in NeoCoV can overcome the incompatibility with human ACE2. In this review, we present a comprehensive overview of ACE2-using merbecoviruses, summarize our current knowledge regarding receptor usage and host tropism determination, and deliberate on potential strategies for prevention and intervention, with the goal of mitigating potential future outbreaks caused by spillover of these viruses.

Keywords: ACE2; Bats; Cross-species transmission; Host tropism; Merbecoviruses; NeoCoV; Receptor.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Geographic origins and phylogenetic relationships of representative merbecoviruses. (a) The discovery locations of representative merbecoviruses and their host species are depicted. (b) Phylogenetic trees illustrating the evolutionary relationships among representative merbecoviruses based on their genomic sequences (upper tree) or RBD protein sequences (lower tree). GeneBank or NGDC-GWH accession numbers are provided. Blue background: DPP4-using; pink background: ACE2-using.
Fig. 2
Fig. 2
Comparison of the receptor binding modes of representativeACE2-usingandDPP4-usingmerbecoviruses. The core domain of RBDs are colored in light gray, while the RBMs and receptors are marked in different colors. The α-helix or equivalent sequences critical for receptor determinantion are highlighted in red. Dashed-line ellipses indicate the two featured RBM loop extensions in MOW15-22 and PnNL 2018B.
Fig. 3
Fig. 3
Structures ofACE2-usingviruses' RBD in complex with human or Bat (P. pipistrellus) ACE2. The structures of the RBD-ACE2 complexes for SARS-CoV, SARS-CoV-2, NL63-CoV, NeoCoV and PDF-2180 are color-coded. RBD binding footprints on ACE2 orthologues are highlighted in corresponding colors.
Fig. 4
Fig. 4
Potential host tropism ofACE2-usingmerbecoviruses across 102 different mammalian species. Phylogenic trees of ACE2 protein sequences from 102 mammals, including 49 bats (a) and 53 non-bat mammals (b), generated by IQ-Tree (http://igtree.cibiv.univie.ac.at/) and polished with iTOL (v6) (https://itol.embl.de/) (Letunic & Bork, 2021). Heatmaps illustrate the pseudovirus entry-supporting abilities of ACE2 orthologues for indicated ACE2-using merbecoviruses, normalized based on our previous reports with the entry efficiencies of the most capable ACE2 set as 100%26,40 27. Species orders (for non-bat mammals) or families (for bats) are indicated. Complete species names corresponding to the four-letter abbreviations are provided in Table S1.
Fig. 5
Fig. 5
Host range determinants for NeoCoV and PDF-2180 on different ACE2. (a) Four determinants of P. pipistrellus ACE2 are indicated by different colors. (b) A diagram displaying the determinant sequences from P. pipistrellus ACE2 and ACE2 orthologues with unfavorable residues in indicated determinants. The glycans and defect types (based on previous reports) are indicated, and the residue numbers are based on P. pipistrellus ACE2 sequences.
Fig. 6
Fig. 6
Hypothesis for the recombination driving the origin of MERS-CoV. Upper: Protein-coding region boundaries for the three merbecoviruses are indicated. Below: Simplot analysis comparing the similarity of complete genome nucleotide sequences of NeoCoV and HKU4 with MERS-CoV. The dashed box outlines regions of the spike protein with notable divergence.
Fig. 7
Fig. 7
Entry inhibitors targeting NeoCoV receptor recognition in human cells. Efficient inhibition of NeoCoV pseudovirus entry can be achieved using soluble P. pipistrellus ACE2, NeoCoV RBD-hFc recombinant proteins, human ACE2 targeting-antibody (H11B11), Pan-β broadly neutralizing antibodies (S2P6, B6 and 76E1), but not MERS-CoV RBD specific nanobodies and SARS-CoV-2 antisera from vaccinated individuals. Specific antibodies targeting ACE2-using merbecoviruses remains to be developed.
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