Biology subjects

Ragotte, R.

Publications and source records attributed to Ragotte, R..

3 recordsLinked to original sources

bioRxiv2026

Computational design of potent, broadly neutralizing anti-Nipah virus and Hendra virus miniproteins

The prototype members of the genus Henipavirus, Nipah virus (NiV) and Hendra virus (HeV), cause recurrent zoonotic spillovers with case fatality rates ranging from 40-90% in humans. Currently, there are no approved vaccines or therapeutics for use in humans. Neutralizing antibodies targeting the NiV/HeV F- or G-glycoproteins protect animals from lethal challenge and are a main correlate of protection. However, antibody-based formulations are expensive, typically requiring hospital admission for administration and cold-chain for storage and transportation. To address the lack of shelf-stable clinical countermeasures, we computationally designed thermostable miniproteins that cross-react with subnanomolar affinities with both NiV and HeV F and G glycoproteins and inhibit viral entry in vitro with potencies comparable to lead antibodies. Oligomerized forms of these miniproteins have enhanced potency relative to their monomeric building blocks and increase the barrier for emergence of escape mutants, establishing them as promising preclinical candidates against these deadly viruses.

bioengineering↗

bioRxiv2024

Target-conditioned diffusion generates potent TNFR superfamily antagonists and agonists

Despite progress in designing protein binding proteins, the shape matching of designs to targets is lower than in many native protein complexes, and design efforts have failed for TNF receptor (TNFR1) and other protein targets with relatively flat and polar surfaces. We hypothesized that free diffusion from random noise could generate shape-matched binders for challenging targets, and tested this on TNFR1. We obtain designs with low picomolar affinity whose specificity can be completely switched to other family members using partial diffusion. Designs function as antagonists or as superagonists when presented at higher valency for OX40 and 4-1BB. The ability to design high-affinity and specificity antagonists and agonists for pharmacologically important targets in silico presages a new era in which binders are made by computation rather than immunization or random screening approaches.

biochemistry↗

bioRxiv2023

Structure of the PfRCR complex which bridges the malaria parasite and erythrocyte during invasion

The symptoms of malaria occur during the blood stage of infection, when parasites invade and replicate within human erythrocytes. The five-component PfPCRCR complex, containing PfRH5, PfCyRPA, PfRIPR, PfCSS and PfPTRAMP, is essential for erythrocyte invasion by the deadliest human malaria parasite, Plasmodium falciparum. Invasion can be prevented by antibodies or nanobodies against each of these five conserved proteins, making them the leading blood stage malaria vaccine candidates. However, little is known about the molecular mechanism by which PfPCRCR functions during invasion. Here we present the structure of the PfRCR complex, containing PfRH5, PfCyRPA and PfRIPR, determined by cryogenic-electron microscopy. This reveals that PfRIPR consists of an ordered multi-domain core flexibly linked to an elongated tail. We test the hypothesis that PfRH5 opens to insert into the membrane, but instead show that a rigid, disulphide-locked PfRH5 can mediate efficient erythrocyte invasion. Finally, we show that the elongated tail of PfRIPR, which is the target of growth- neutralising antibodies, binds to the PfCSS-PfPTRAMP complex on the parasite membrane. Therefore, a modular PfRIPR is linked to the merozoite membrane through an elongated tail, while its structured core presents PfCyRPA and PfRH5 to interact with erythrocyte receptors. This provides novel insight into the mechanism of erythrocyte invasion and opens the way to new approaches in rational vaccine design.

microbiology↗