Crystal Structure of Cleaved Serp-1, a Myxomavirus-Derived Immune Modulating Serpin: Structural Design of Serpin Reactive Center Loop Peptides with Improved Therapeutic Function
The Myxomavirus-derived protein Serp-1 has potent anti-inflammatory activity in models of vasculitis, lupus, viral sepsis, and transplant. Serp-1 has also been tested successfully in a Phase IIa clinical trial in unstable angina, representing a 'first-in-class' therapeutic. Recently, peptides derived from the reactive center loop (RCL) have been developed as stand-alone therapeutics for reducing vasculitis and improving survival in MHV68-infected mice. However, both Serp-1 and the RCL peptides lose activity in MHV68-infected mice after antibiotic suppression of intestinal microbiota. Here, we utilize a structure-guided approach to design and test a series of next generation RCL peptides with improved therapeutic potential that is not reduced when combined with antibiotic treatments. The crystal structure of the cleaved Serp-1 was determined to 2.5 Å resolution, and reveals a classical serpin structure with potential for serpin-derived RCL peptides to bind and inhibit mammalian serpins, plasminogen activator inhibitor 1 (PAI-1), anti-thrombin III (ATIII) and alpha-1 antitrypsin (A1AT) and target proteases. Using in silico modeling of Serp-1 RCL peptide, S-7, we designed several modified RCL peptides that were predicted to have stronger interactions with human serpins due to a higher number of stabilizing hydrogen bonds. Two of these peptides (MPS7-8 and -9) displayed extended activity, improving survival where activity was previously lost in antibiotic treated MHV68-infected mice (P < 0.0001). Mass spectrometry and kinetic assays suggest peptide interaction with ATIII, A1AT, and target proteases in mouse and human plasma. In summary, we present the next step towards the development of a promising new class of anti-inflammatory serpin-based therapeutic.
Pharmacology, Toxicology and Pharmaceutical Science
2
6%
Nursing and Health Professions
2
6%
Computer Science
2
6%
Other
6
19%
Unknown
10
32%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 11. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 13 May 2025.
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#4,011,710
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#1,506
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#69,829
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#20
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Altmetric has tracked 31,634,113 research outputs across all sources so far. Compared to these this one has done well and is in the 87th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 25,636 research outputs from this source. They receive a mean Attention Score of 4.7. This one has done particularly well, scoring higher than 94% of its peers.
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