Stabilized polypeptides as regulators of RAB GTPase function
First Claim
Patent Images
1. An unstapled polypeptide of Formula (I):
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Rf-[XAA]s-[X1-26]-[XAA]t-Re
(I)or a pharmaceutically acceptable salt thereof;
wherein;
each instance of XAA is a natural amino acid or an unnatural amino acid;
s is 0 or an integer between 1 and 100, inclusive;
t is 0 or an interger between 1 and 100, inclusive;
Rf is an N-terminal group selected from the group consisting of hydrogen;
optionally substituted aliphatic;
optionally substituted heteroaliphatic;
optionally substituted aryl;
optionally substituted heteroaryl;
acyl;
a resin;
an amino protecting group; and
a label optionally joined by a linker, wherein the linker is selected from the group consisting of optionally substituted alkylene;
optionally substituted alkenylene;
optionally substituted alkynylene;
optionally substituted heteroalkylene;
optionally substituted heteroalkenylene;
optionally substituted heteroalkynylene;
optionally substituted arylene;
optionally substituted heteroarylene; and
acylene;
Re is a C-terminal group selected from the group consisting of hydrogen;
optionally substituted aliphatic;
optionally substituted heteroaliphatic;
optionally substituted aryl;
optionally substituted heteroaryl;
—
ORE, —
N(RE)2, or —
SRE, wherein each instance of RE is, independently, hydrogen;
optionally substituted aliphatic;
optionally substituted heteroaliphatic;
optionally substituted aryl;
optionally substituted heteroaryl;
acyl;
a resin;
a protecting group;
or two RE groups taken together form an optionally substituted heterocyclic or optionally substituted heteroaryl ring;
-[X1-26]- is an unstapled amino acid sequence of the formula;
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Abstract
The present invention provides inventive polypeptides comprising a C terminal RAB binding domain (RabBD) of RAB family interacting proteins (FIPs) stabilized by peptide stapling, and pharmaceutical compositions thereof. Also provided are methods for modulating RAB function comprising contacting an inventive stapled polypeptide with a RAB protein, and methods of treatment associated with modulation of RAB activity. The present invention also provides methods of making the inventive stapled polypeptides by ring closing metathesis of unstapled polypeptide precursors.
102 Citations
34 Claims
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1. An unstapled polypeptide of Formula (I):
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Rf-[XAA]s-[X1-26]-[XAA]t-Re
(I)or a pharmaceutically acceptable salt thereof; wherein; each instance of XAA is a natural amino acid or an unnatural amino acid; s is 0 or an integer between 1 and 100, inclusive; t is 0 or an interger between 1 and 100, inclusive; Rf is an N-terminal group selected from the group consisting of hydrogen;
optionally substituted aliphatic;
optionally substituted heteroaliphatic;
optionally substituted aryl;
optionally substituted heteroaryl;
acyl;
a resin;
an amino protecting group; and
a label optionally joined by a linker, wherein the linker is selected from the group consisting of optionally substituted alkylene;
optionally substituted alkenylene;
optionally substituted alkynylene;
optionally substituted heteroalkylene;
optionally substituted heteroalkenylene;
optionally substituted heteroalkynylene;
optionally substituted arylene;
optionally substituted heteroarylene; and
acylene;Re is a C-terminal group selected from the group consisting of hydrogen;
optionally substituted aliphatic;
optionally substituted heteroaliphatic;
optionally substituted aryl;
optionally substituted heteroaryl;
—
ORE, —
N(RE)2, or —
SRE, wherein each instance of RE is, independently, hydrogen;
optionally substituted aliphatic;
optionally substituted heteroaliphatic;
optionally substituted aryl;
optionally substituted heteroaryl;
acyl;
a resin;
a protecting group;
or two RE groups taken together form an optionally substituted heterocyclic or optionally substituted heteroaryl ring;-[X1-26]- is an unstapled amino acid sequence of the formula; - View Dependent Claims (25, 26, 27, 28, 29, 30, 31, 32)
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2. A stapled polypeptide of the Formula (II):
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Rf-[XAA]s-[X1-26]-[XAA]t-Re
(II)or a pharmaceutically acceptable salt thereof; wherein; each instance of XAA is a natural amino acid or unnatural amino acid; s is 0 or an integer between 1 and 100, inclusive; t is 0 or an integer between 1 and 100, inclusive; Rf is an N-terminal group selected from the group consisting of hydrogen;
optionally substituted aliphatic;
optionally substituted heteroaliphatic;
optionally substituted aryl;
optionally substituted heteroaryl;
acyl;
a resin;
an amino protecting group; and
a label optionally joined by a linker, wherein the linker is selected from the group consisting of optionally substituted alkylene;
optionally substituted alkenylene;
optionally substituted alkynylene;
optionally substituted heteroalkylene;
optionally substituted heteroalkenylene;
optionally substituted heteroalkynylene;
optionally substituted arylene;
optionally substituted heteroarylene; and
acylene;Re is a C-terminal group selected from the group consisting of hydrogen;
optionally substituted aliphatic;
optionally substituted heteroaliphatic;
optionally substituted aryl;
optionally substituted heteroaryl;
—
ORE, —
N(RE)2, or —
SRE, wherein each instance of RE is, independently, hydrogen;
optionally substituted aliphatic;
optionally substituted heteroaliphatic;
optionally substituted aryl;
optionally substituted heteroaryl;
acyl;
a resin;
a protecting group;
or two RE groups taken together form an optionally substituted heterocyclic or optionally substituted heteroaryl ring; and-[X1-26]- is a stapled amino sequence of the Formula; - View Dependent Claims (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 33, 34)
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Specification