US 11,584,776 B2Granted

Methods and systems for solid phase peptide synthesis

AssigneeMassachusetts Institute of Technology

InventorsDale Arlington Thomas, III, Alexander James Mijalis, Bradley L. Pentelute, Mark David Simon, Surin Mong

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Abstract

Methods and systems for control of solid phase peptide synthesis are generally described. Control of solid phase peptide synthesis involves the use of feedback from one or more reactions and/or processes (e.g., reagent removal) taking place in the solid phase peptide synthesis system. In some embodiments, a detector may detect one or more fluids flowing across a detection zone of a solid phase peptide synthesis system and one or more signals may be generated corresponding to the fluid(s). For instance, an electromagnetic radiation detector positioned downstream of a reactor may detect a fluid exiting the reactor after a deprotection reactor and produce a signal(s). In some embodiments, based at least in part on information derived from the signal(s), a parameter of the system may be modulated prior to and/or during one or more subsequent reactions and/or processes taking place in the solid phase peptide synthesis system. In some embodiments, the methods and systems, described herein, can be used to conduct quality control to determine and correct problems (e.g., aggregation, truncation, deletion) in reactions (e.g., coupling reactions) taking place in the solid phase peptide synthesis system.

Claims46

Dependent claims

A method of operating a peptide synthesis system, comprising:

performing a first amino acid addition cycle of a first peptide synthesis process to synthesize a peptide on a solid support in a reactor, the first amino acid addition cycle comprising a first deprotection reaction, a first coupling reaction, and one or more first optional reagent removal steps;
detecting, during the first amino acid addition cycle of the first peptide synthesis process, an electromagnetic absorbance and/or an electromagnetic emission of a fluid stream at a detection zone positioned downstream of the reactor to produce a reference signal comprising a reference peak;
performing a second amino acid addition cycle of the first peptide synthesis process or of a second peptide synthesis process, the second amino acid addition cycle comprising a second deprotection reaction, a second coupling reaction, and one or more second optional reagent removal steps;
detecting, during the second amino acid addition cycle, an electromagnetic absorbance and/or an electromagnetic emission of a fluid stream at the detection zone positioned downstream of the reactor to produce a signal comprising a first peak;
determining whether improper resin loading and/or a mechanical failure has occurred during the second coupling reaction based at least in part on a comparison between a property of the first peak and a corresponding property of a reference peak;
and
stopping the peptide synthesis process that included the second amino acid addition cycle and starting a subsequent peptide synthesis process if the comparison indicates that improper resin loading and/or a mechanical failure has occurred during the second coupling reaction.

4 more elements

A method of operating a peptide synthesis system, comprising:

performing a first amino acid addition cycle of a first peptide synthesis process to synthesize a peptide on a solid support in a reactor, the first amino acid addition cycle comprising a first deprotection reaction, a first coupling reaction, and one or more first optional reagent removal steps;
detecting, during the first amino acid addition cycle of the first peptide synthesis process, an electromagnetic absorbance and/or an electromagnetic emission of a fluid stream at a detection zone positioned downstream of the reactor to produce a reference signal comprising a reference peak;
performing a second amino acid addition cycle of the first peptide synthesis process or of a second peptide synthesis process, the second amino acid addition cycle comprising a second deprotection reaction, a second coupling reaction, and one or more second optional reagent removal steps;
detecting, during the second amino acid addition cycle, an electromagnetic absorbance and/or an electromagnetic emission of a fluid stream at the detection zone positioned downstream of the reactor to produce a signal comprising a first peak;
comparing a property of the first peak and a corresponding property of the reference peak;
and
based at least in part on the comparing, stopping the peptide synthesis process that included the second amino acid addition cycle and/or performing at least one of the following during a coupling reaction of a subsequent peptide synthesis process to synthesize the peptide, the coupling reaction of the subsequent peptide synthesis process corresponding to the coupling reaction of the peptide synthesis process that included the second amino acid addition cycle:
increasing a residence time of an activating agent;
and/or
employing a different activating agent;
and/or
increasing a temperature of the reactor and/or the fluid stream;
and/or
employing a different stoichiometric ratio.

11 more elements

A method of operating a peptide synthesis system, comprising:

performing a first amino acid addition cycle of a first peptide synthesis process to synthesize a peptide on a solid support in a reactor, the first amino acid addition cycle comprising a first deprotection reaction, a first coupling reaction, and one or more first optional reagent removal steps;
detecting, during the first amino acid addition cycle of the first peptide synthesis process, an electromagnetic absorbance and/or an electromagnetic emission of a fluid stream at a detection zone positioned downstream of the reactor to produce a reference signal comprising a reference peak;
performing a second amino acid addition cycle of the first peptide synthesis process or of a second peptide synthesis process, the second amino acid addition cycle comprising a second deprotection reaction, a second coupling reaction, and one or more second optional reagent removal steps;
detecting, during the second amino acid addition cycle, an electromagnetic absorbance and/or an electromagnetic emission of a fluid stream at the detection zone positioned downstream of the reactor to produce a signal comprising a first peak;
comparing a property of the first peak and a corresponding property of the reference peak;
and
based at least in part on the comparing, increasing a temperature of the reactor and/or a fluid stream entering the reactor.

4 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/874,824Filed 15 May 2020 · continuation
Priority: 17 Sep 2015
Published: US 2021/0047365 A118 Feb 2021
Granted: 21 Feb 2023
Term ends: Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07K 1/045
On carriers: using devices to improve synthesis, e.g. reactors, special vessels
C07K 7/06
Linear peptides containing only normal peptide links: having 5 to 11 amino acids
C07K 14/47
From vertebrates: from mammals
C07K 14/60
Hormones: growth hormone-releasing factor [GH-RF], i.e. somatoliberin

Family

Application62/220,233Us provisional application · filed 17 Sep 2015
Application15/268,032Parent of this continuation · filed 16 Sep 2016
US 2021/0047365 A1Pre-grant publication · published 18 Feb 2021
US 10,683,325 B2Parent of this continuation
US 2017/0081358 A1Published application
US 11,584,776 B2This patent

From the US filing history. Foreign family members aren’t listed.