Cationic Steroidal Antimicrobial Compounds Protease Stability

Solution Overview

Problem

Current antimicrobial peptides face challenges such as high production costs, susceptibility to proteases, and deactivation by proteins and DNA in lung mucosa, limiting their clinical use, prompting the need for non-peptide mimics that maintain broad-spectrum antibacterial activity while being more stable and cost-effective.

Innovation Solution

Development of cationic steroidal antimicrobial (CSA) compounds with amide functionality, specifically compounds like CSA-190, CSA-191, CSA-192, and CSA-192MS, which have a steroidal backbone with amide groups positioned between the amido nitrogen and fused ring D, offering improved antimicrobial activity and simplified synthesis compared to existing compounds.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If antimicrobial peptides are used for broad-spectrum antibacterial activity, then antibacterial efficacy is improved, but production cost increases and stability against proteases decreases

Engineering Contradiction:

Improveantibacterial efficacyVSAvoidproduction cost

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent creates non-peptide mimic compounds (ceragenins) that copy the essential amphiphilic morphology and cationic character of antimicrobial peptides without using peptide bonds. These small molecule compounds replicate the antibacterial function while being synthetically accessible through conventional organic chemistry, thereby maintaining efficacy while dramatically reducing production cost and eliminating protease susceptibility.

Inventive Principle:

Principle #26Copying

Solution Approach 2:

The invention changes the fundamental chemical parameters from peptide-based structures with amide bonds to small molecule structures with amine or guanidine cationic groups. This parameter change transforms the compounds from protease-sensitive peptides to protease-stable small molecules, while maintaining the critical amphiphilic morphology needed for antibacterial activity through structural design featuring a planar or nearly planar cationic face.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If antimicrobial peptides are used for broad-spectrum antibacterial activity, then antibacterial efficacy is improved, but susceptibility to proteases increases

Engineering Contradiction:

Improveantibacterial efficacyVSAvoidprotease stability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent creates non-peptide mimic compounds (ceragenins) that copy the essential amphiphilic morphology and cationic character of antimicrobial peptides without using peptide bonds. These small molecule compounds replicate the antibacterial function while being synthetically accessible through conventional organic chemistry, thereby maintaining efficacy while dramatically reducing production cost and eliminating protease susceptibility.

Inventive Principle:

Principle #26Copying

Solution Approach 2:

The invention replaces complex, biologically-derived peptide structures with simple, synthetically-accessible small molecule structures. These small molecules achieve the same biological function at lower molecular weight and simpler structure, making them inherently more stable to proteolytic degradation while maintaining broad-spectrum antibacterial activity.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

3Reliability

If antimicrobial peptides are used for broad-spectrum antibacterial activity, then antibacterial efficacy is improved, but deactivation by proteins and DNA in lung mucosa increases

Engineering Contradiction:

Improveantibacterial efficacyVSAvoidduration of action

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The invention changes the fundamental chemical parameters from peptide-based structures with amide bonds to small molecule structures with amine or guanidine cationic groups. This parameter change transforms the compounds from protease-sensitive peptides to protease-stable small molecules, while maintaining the critical amphiphilic morphology needed for antibacterial activity through structural design featuring a planar or nearly planar cationic face.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS9434759B1Cationic steroidal antimicrobial compounds and methods of manufacturing such compounds

Publication Date: 2016.09.06 BRIGHAM YOUNG UNIV

AI summary

Cationic steroidal antimicrobial (CSA) compounds having amide functionality and methods of manufacturing such CSA compounds. The CSA compound can be a compound of Formula (I), Formula (II), Formula (III), or a salt thereof:where R18 has the following structure:—R20—(C═O)—N—R21R22 R20 is omitted or substituted or unsubstituted alkyl, alkenyl, alkynyl, or aryl, andR21 and R22 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted aryl, provided that at least one of R21 and R22 is not hydrogen.