Synthesis of “Nereid,” a new phenol‐free detergent to replace Triton X‐100 in virus inactivation

Abstract

In the 1980s, virus inactivation steps were implemented into the manufacturing of biopharmaceuticals in response to earlier unforeseen virus transmissions. The most effective inactivation process for lipid‐enveloped viruses is the treatment by a combination of detergents, often including Triton X‐100 (TX‐100). Based on recent environmental concerns, the use of TX‐100 in Europe will be ultimately banned, which forces the pharmaceutical industry, among others, to switch to an environmentally friendly alternative detergent with fully equivalent virus inactivation performance such as TX‐100. In this study, a structure–activity relationship study was conducted that ultimately led to the synthesis of several new detergents. One of them, named “Nereid,” displayed inactivation activity fully equivalent to TX‐100. The synthesis of this replacement candidate has been optimized to allow for the production of several kg of detergent at lab scale, to enable the required feasibility and comparison virus inactivation studies needed to support a potential future transition. The 3‐step, chromatography‐free synthesis process described herein uses inexpensive starting materials, has a robust and simple work‐up, and allows production in a standard organic laboratory to deliver batches of several hundred grams with >99% purity.

Orthopox viruses and the safety margins of solvent‐detergent treated plasma‐derived medicinal products

“…The current investigation provides for a comprehensive verification of the effectiveness of TX‐100‐based poxvirus inactivation. In addition, we confirm that a potential future replacement for TX‐100, Nereid, 6,7 which will become necessary because of environmental concerns about the use of TX‐100, is equally effective in inactivation of a worst‐case lipid‐enveloped virus, that is, the poxvirus model vaccinia virus.…”

“…Taking the ratio of S/D components into account, this mixture was investigated in the down‐scale at final concentrations of 50% or 10% of the target manufacturing concentration. Similar experiments were done with a second S/D reagent mix where TX‐100 was replaced by Nereid, a proprietary compound synthesized by Takeda's R&D group 7,10 . The process intermediate was tempered to 17°C, spiked with VACV at a ratio of 31:1, and weighed to calculate the necessary amount of S/D mix to be added.…”

Supported Lipid Bilayer Platform for Characterizing the Membrane-Disruptive Behaviors of Triton X-100 and Potential Detergent Replacements

“…Accordingly, to test detergent candidates, the major focus has been on treating selected membrane-enveloped viruses with different detergent concentrations under varying environmental conditions and exposure times and measuring the resulting effects on viral infectivity. This experimental approach has led to identifying several detergents with potentially suitable virus-inactivating properties, including the following two compounds: (1) Simulsol SL 11W (SL-11W), which is a commercially available glycoside surfactant that consists of an 11-carbon long, fatty alcohol joined together with a glucose molecule [ 12 ]; and (2) Nereid, which is a recently developed, phenol-free detergent that is structurally similar to TX-100 and not yet commercially available [ 13 ]. Depending on the study, the detergent candidates have either been tested alone or in direct comparison with TX-100, and the quantitative basis for performance evaluation has been the magnitude of the drop in viral infectivity and the corresponding inactivation kinetics.…”

Pharmacomodulation of a ligand targeting the HBV capsid hydrophobic pocket

“…Alternatives to TX100 are currently under development, as for instance the new detergent Nereid, an environmentally-friendly replacement candidate for TX100 based on substitution of the phenol with a benzylic alcohol. 31 Interestingly, we here show that the benzylic alcohol version (compound 1d) retains strong binding capacity to Cp, which points out a direction towards less endocrine-disrupting Cp pocket binders.…”