Multivalent designed proteins protect against SARS-CoV-2 variants of concern

Hunt, Andrew C.; Case, James Brett; Park, Young-Jun; Cao, Longxing; Wu, Ke‐Jia; Walls, Alexandra C.; Liu, Zhuoming; Bowen, John E.; Yeh, Hsien‐Wei; Saini, Shally; Helms, Louisa; Zhao, Yan Ting; Hsiang, Tien-Ying; Starr, Tyler N; Goreshnik, Inna; Kozodoy, Lisa; Carter, Lauren; Ravichandran, Rashmi; Green, Lydia B.; Matochko, Wadim L.; Thomson, Christy A.; Vogeli, Bastain; Kruger-Gericke, Antje; VanBlargan, Laura A.; Chen, Rita E.; Bai, Ying; Bailey, Adam L.; Kafai, Natasha M.; Boyken, Scott E.; Ljubetič, Ajasja; Edman, Natasha I.; Ueda, George; Chow, Cameron M.; Addetia, Amin; Panpradist, Nuttada; Gale, Michael; Freedman, Benjamin; Lutz, Barry; Bloom, Jesse D; Ruohola‐Baker, Hannele; Whelan, Sean P. J.; Stewart, Lance; Diamond, Michael S.; Veesler, David; Jewett, Michael C.; Baker, David

doi:10.1101/2021.07.07.451375

Cited by 18 publications

(9 citation statements)

References 97 publications

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“…LCB1 was designed specifically against the receptor-binding domain of the SARS-CoV-2/WA1 variant isolated in 2020. As variants emerge, these spike binder proteins may lose their potency if critical binding domains are mutated, necessitating new designs ( 85 ).…”

Section: Discussionmentioning

confidence: 99%

“…Data from a controlled human cohort of COVID-19 patients support the physiological relevance of the findings in organoids. The remarkable tropism observed in these organoids, their ability to reveal physiologically relevant injury, and their accessibility to genome editing, together with the availability of urine samples from patients for proteomic analysis, combine to establish a powerful system for studying COVID-19 renal pathophysiology and developing therapeutics ( 19 , 22 , 85 ).…”

Section: Discussionmentioning

confidence: 99%

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Cross-validation of SARS-CoV-2 responses in kidney organoids and clinical populations

Helms¹,

Marchianò²,

Stanaway³

et al. 2021

JCI Insight

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Kidneys are critical target organs of COVID-19, but susceptibility and responses to infection remain poorly understood. Here, we combine SARS-CoV-2 variants with genome-edited kidney organoids and clinical data to investigate tropism, mechanism, and therapeutics. SARS-CoV-2 specifically infects organoid proximal tubules among diverse cell types. Infections produce replicating virus, apoptosis, and disrupted cell morphology, features of which are revealed in the context of polycystic kidney disease. Cross-validation of gene expression patterns in organoids reflects proteomic signatures of COVID-19 in the urine of critically ill patients indicating interferon pathway upregulation. SARS-CoV-2 viral variants alpha, beta, gamma, kappa, and delta exhibit comparable levels of infection in organoids. Infection is ameliorated in ACE2–/– organoids and blocked via treatment with de novo–designed spike binder peptides. Collectively, these studies clarify the impact of kidney infection in COVID-19 as reflected in organoids and clinical populations, enabling assessment of viral fitness and emerging therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cross-validation of SARS-CoV-2 responses in kidney organoids and clinical populations

Helms¹,

Marchianò²,

Stanaway³

et al. 2021

JCI Insight

Self Cite

View full text Add to dashboard Cite

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“…At present, several vaccines for SARS-CoV-2 have been put on the market. However, the virus is prone to mutation and its genome is characterised by high diversity and frequent recombination, leading to weak protective power and insufficient duration of protection 7 . Additionally, frequent cross-species transmission further emphasises the importance of fundamental preventive and therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

Potential Genes Associated with COVID-19 and Comorbidity

Feng¹,

Song²,

Guo³

et al. 2022

Int. J. Med. Sci.

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Hypertension, diabetes mellitus, and coronary artery disease are common comorbidities and dangerous factors for infection and serious COVID-19. Polymorphisms in genes associated with comorbidities may help observe susceptibility and disease severity variation. However, specific genetic factors and the extent to which they can explain variation in susceptibility of severity are unclear. Therefore, we evaluated candidate genes associated with COVID-19 and hypertension, diabetes mellitus, and coronary artery disease. In particular, we performed searches against OMIM, NCBI, and other databases, protein-protein interaction network construction, and GO and KEGG pathway enrichment analyses. Results showed that the associated overlapping genes were TLR4, NLRP3, MBL2, IL6, IL1RN, IL1B, CX3CR1, CCR5, AGT, ACE, and F2. GO and KEGG analyses yielded 302 GO terms (q < 0.05) and 29 signaling pathways (q < 0.05), respectively, mainly including coronavirus disease-COVID-19 and cytokine-cytokine receptor interaction. IL6 and AGT were central in the PPI, with 8 and 5 connections, respectively. In this study, we identified 11 genes associated with both COVID-19 and three comorbidities that may contribute to infection and disease severity. The key genes IL6 and AGT are involved in regulating immune response, cytokine activity, and viral infection. Therefore, RAAS inhibitors, AGT antisense nucleotides, cytokine inhibitors, vitamin D, fenofibrate, and vaccines regulating non-immune and immune factors could be potential strategies to prevent and cure COVID-19. The study provides a basis for further investigation of genes and pathways with predictive value for the risk of infection and prognosis and could help guide drug and vaccine development to improve treatment efficacy and the development of personalised treatments, especially for COVID-19 individuals with common comorbidities.

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“…The results of the SARS-CoV-2 pseudovirus neutralization assays showed that the binding enhancement observed in the trimeric assembly translated into increased neutralization ability when compared to both the genetically conjugated and GCE-conjugated dimers. Similarly, a recent study using designed RBD mini-binders also showed that SARS-CoV-2 neutralization was improved by trimerization, and that the topology of trimerization mattered, although, in that case, the topologies tested were all limited to genetic linkages through the N and C termini ( 34 ).…”

Section: Discussionmentioning

confidence: 94%

Nanobody assemblies with fully flexible topology enabled by genetically encoded tetrazine amino acids

et al. 2022

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Assembling nanobodies (Nbs) into polyvalent multimers is a powerful strategy for improving the effectiveness of Nb-based therapeutics and biotechnological tools. However, generally effective approaches to Nb assembly are currently restricted to the amino or carboxyl termini, greatly limiting the diversity of Nb multimer topologies that can be produced. Here, we show that reactive tetrazine groups—site-specifically inserted by genetic code expansion at Nb surface sites—are compatible with Nb folding and function, enabling Nb assembly at any desired point. Using two anti–SARS-CoV-2 Nbs with viral neutralization ability, we created Nb homo- and heterodimers with improved properties compared with conventionally linked Nb homodimers, which, in the case of our tetrazine-conjugated trimer, translated into enhanced viral neutralization. Thus, this tetrazine-based approach is a generally applicable strategy that greatly increases the accessible range of Nb assembly topologies, and thereby adds the optimization of topology as an effective avenue to generate Nb assemblies with improved efficacy.

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Multivalent designed proteins protect against SARS-CoV-2 variants of concern

Cited by 18 publications

References 97 publications

Cross-validation of SARS-CoV-2 responses in kidney organoids and clinical populations

Cross-validation of SARS-CoV-2 responses in kidney organoids and clinical populations

Potential Genes Associated with COVID-19 and Comorbidity

Nanobody assemblies with fully flexible topology enabled by genetically encoded tetrazine amino acids

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