Bovine viral diarrhea virus (BVDV) is a major pathogen in cattle herds, widely distributed across the globe and causing significant economic losses to the cattle industry. The nonstructural protein NS3 is highly conserved across BVDV subtypes. Identifying and screening epitopes on BVDV NS3 is crucial for developing sensitive, specific diagnostic tools. In this study, we obtained three monoclonal antibodies (mAbs) against the NS3 protein: 2F7, 3E8, and 4D6. Three novel linear B-cell epitope ¹⁰⁰EYG¹⁰², ³⁸⁴FLDIA³⁸⁸, and ¹⁰⁰EYGVK¹⁰⁴ were identified through reactions of these mAbs with a series of continuous-truncated peptides and one of which a rare three-amino-acid B-cell epitope ¹⁰⁰EYG¹⁰². Critical amino acid residues were further characterized through alanine (A)-scanning mutagenesis. Sequence alignment revealed that ¹⁰⁰EYG¹⁰² and ¹⁰⁰EYGVK¹⁰⁴ were highly conserved allowing mAbs 2F7 and 4D6 to recognize all BVDV subtypes. In contrast, ³⁸⁴FLDIA³⁸⁸ was specifically conserved in BVDV-1 and BVDV-3 enabling 3E8 mAb to differential diagnosis BVDV-2 from other BVDV subtypes. Additionally, preliminary diagnostic assays for BVDV were established by western blotting and peptide-based blocking ELISA. Moreover, we observed that these mAbs could inhibit the replication of BVDV. These findings provide a theoretical foundation for developing of therapeutic strategies for nonstructural protein and accurate diagnostic procedures.

27 Jul 2023·Journal of medicinal chemistryQ1 · MEDICINE

Structure-Guided Chemical Optimization of Bicyclic Peptide (Bicycle) Inhibitors of Angiotensin-Converting Enzyme 2.

Q1 · MEDICINE

Article

Author: Brear, Paul ; Stanway, Steven J ; Harman, Maximilian A J ; Pellegrino, Simone ; Skynner, Michael J ; Chen, Liuhong ; Beswick, Paul J ; Demydchuk, Yuliya ; Scott, Heather ; Hyvönen, Marko ; Bezerra, Gustavo Arruda ; Lulla, Aleksei

Angiotensin-converting enzyme 2 (ACE2) is a metalloprotease that cleaves angiotensin II, a peptide substrate involved in the regulation of hypertension. Here, we identified a series of constrained bicyclic peptides, Bicycle, inhibitors of human ACE2 by panning highly diverse bacteriophage display libraries. These were used to generate X-ray crystal structures which were used to inform the design of additional Bicycles with increased affinity and inhibition of ACE2 enzymatic activity. This novel structural class of ACE2 inhibitors is among the most potent ACE2 inhibitors yet described in vitro, representing a valuable tool to further probe ACE2 function and for potential therapeutic utility.

11 Apr 2023·Blood Advances

Anti-HK antibody inhibits the plasma contact system by blocking prekallikrein and factor XI activation in vivo

Article

Author: Horn, Katharina ; Kaneki, Shigeru ; Calvano, Marissa R. ; McCrae, Keith R. ; Strickland, Sidney ; Norris, Erin H. ; Singh, Pradeep K. ; Chen, Zu-Lin

AbstractA dysregulated plasma contact system is involved in various pathological conditions, such as hereditary angioedema, Alzheimer disease, and sepsis. We previously showed that the 3E8 anti–high molecular weight kininogen (anti-HK) antibody blocks HK cleavage and bradykinin generation in human plasma ex vivo. Here, we show that 3E8 prevented not only HK cleavage but also factor XI (FXI) and prekallikrein (PK) activation by blocking their binding to HK in mouse plasma in vivo. 3E8 also inhibited contact system–induced bradykinin generation in vivo. Interestingly, FXII activation was also inhibited, likely because of the ability of 3E8 to block the positive feedback activation of FXII by kallikrein (PKa). In human plasma, 3E8 also blocked PK and FXI binding to HK and inhibited both thrombotic (FXI activation) and inflammatory pathways (PK activation and HK cleavage) of the plasma contact system activation ex vivo. Moreover, 3E8 blocked PKa binding to HK and dose-dependently inhibited PKa cleavage of HK. Our results reveal a novel strategy to inhibit contact system activation in vivo, which may provide an effective method to treat human diseases involving contact system dysregulation.

100 Deals associated with ACE2 inhibitors(University of Chinese Academy of Sciences)

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Indication	Highest Phase	Country/Location	Organization	Date
COVID-19	Preclinical	China	University of Chinese Academy of Sciences	25 Aug 2021

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