Ribosome-Inactivating Protein Inhibitors Targeting the Ribosome Binding Site
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Solution Overview
Problem
Current treatments lack potent inhibitors against ribosome inactivating proteins (RIPs) such as ricin and Shiga toxins, which cause severe toxicity with no FDA-approved vaccines or therapeutics, and existing small-molecule inhibitors are ineffective due to the large active site pocket and strong electrostatic interactions at the RIP-ribosome interface.
Innovation Solution
Development of potent RIP inhibitors targeting the ribosome binding site using fragment-based lead discovery (FBLD) with surface plasmon resonance (SPR) and nuclear magnetic resonance (NMR) to identify low molecular weight fragments that bind to ricin, blocking its interaction with the ribosome and inhibiting depurination activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If small-molecule inhibitors are developed to target RIPs, then the treatment can be administered systemically, but the inhibitors fail to exhibit potent protection due to the large active site pocket and strong electrostatic interactions
Solution Approach 1:
The patent uses a peptide-based intermediary that mimics the ribosomal P-stalk binding interface to mediate inhibition of RIPs. This peptide intermediary competes with the ribosome for binding to the RIP active site, overcoming the limitation of small-molecule inhibitors by providing a more effective binding interface that can achieve potent protection while maintaining systemic administrability
Solution Approach 2:
The patent changes the molecular parameters from small-molecule compounds to peptide-based compounds with specific amino acid sequences. This parameter change allows the inhibitor to better match the binding interface requirements of RIPs, achieving nanomolar to low micromolar inhibition constants while maintaining the ability for systemic administration
2Adaptability or versatility
If no FDA-approved vaccine or therapeutic exists for RIPs, then there is freedom to develop novel treatments, but there is an unmet need for potent RIP-inhibitors to treat toxicity
Solution Approach 1:
The patent segments the ribosomal P-stalk binding interface into a peptide sequence that can be synthesized and administered as a standalone therapeutic. By segmenting the binding interface into discrete amino acid residues that maintain the critical binding interactions, the invention creates a novel therapeutic that can be developed without existing vaccine or treatment constraints
Solution Approach 2:
The patent creates a simplified copy or mimic of the ribosomal P-stalk binding interface using a peptide sequence. This peptide copy retains the essential binding characteristics needed to inhibit RIPs effectively, providing a novel therapeutic approach that addresses the unmet need for potent RIP-inhibitors
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The identified inhibitors exhibit nanomolar protection against RIPs, providing effective treatment and prevention of toxicity by reducing ribosome binding and cytotoxicity, and can be used alone or in combination with immunotherapeutics for enhanced therapeutic efficacy.
Implementation Method 1
fragment-based lead discovery (FBLD) with surface plasmon resonance (SPR)
Implementation Method 2
fragment-based lead discovery (FBLD) with surface plasmon resonance (SPR) and nuclear magnetic resonance (NMR)
Data Source
AI summary
The disclosure provides in one aspect a method of treating, ameliorating, and/or preventing toxicity caused by a ribosome inactivating protein (RIP) in a subject. In certain embodiments, the method comprises administering to the subject a therapeutically effective amount of at least one compound of the disclosure.