The present invention relates to conjugate compounds and methods of making and using same.

Compounds and compositions that have a Protein Recognition Moiety bound to an electrophile for the selective covalent modification of targeted proteins to treat disorders mediated by the targeted protein are described.

The present invention provides TGF- antagonists and conjugates thereof, as well as methods of using such compositions for attenuating TGF- signaling. These novel compositions and methods may be useful for treating individuals suffering from devastating diseases associated with elevated TGF- signaling, including skeletal disorders, such as osteogenesis imperfecta (OI), and muscular diseases, such as muscular dystrophies.

The present invention provides carbonate prodrugs which comprise a carbonic phosphoric anhydride prodrug moiety attached to the hydroxyl or carboxyl group of a parent drug moiety. The prodrugs may provide improved physicochemical properties over the parent drug. Also provided are methods of treating a disease or condition that is responsive to the parent drug using the carbonate prodrugs, as well as kits and unit dosages.

Provided herein are magnetic resonance imaging (MRI) contrast agents comprising a compound having a structure represented by: YXZ, wherein, X is: Fe(III) or Mn(II), and Y and Z are each independently selected from pyrophosphate and bisphosphonate (e.g., 1-hydroxybisphosphonate), or a pharmaceutically acceptable hydrate and/or salt thereof. Methods of use of the MRI contrast agent are also provided.

Among other things, the present disclosure provides designed PNPLA3 oligonucleotides, compositions, and methods thereof. In some embodiments, provided oligonucleotide compositions provide improved single-stranded RNA interference and/or RNase H-mediated knockdown. Among other things, the present disclosure encompasses the recognition that structural elements of oligonucleotides, such as base sequence, chemical modifications (e.g., modifications of sugar, base, and/or internucleotidic linkages) or patterns thereof, conjugation with additional chemical moieties, and/or stereochemistry [e.g., stereochemistry of backbone chiral centers (chiral internucleotidic linkages)], and/or patterns thereof, can have significant impact on oligonucleotide properties and activities, e.g., RNA interference (RNAi) activity, stability, delivery, etc. In some embodiments, the present disclosure provides methods for treatment of diseases using provided oligonucleotide compositions, for example, in RNA interference and/or RNase H-mediated knockdown.

Provided herein are conjugated oligonucleotides that are characterized by efficient and specific eye distribution.

Provided are an RNA inhibitor for inhibiting hepatitis B virus (HBV) gene expression and an application thereof. The RNA inhibitor is formed of a sense strand and an antisense strand by means of base pairing; the sense strand and the antisense strand are at least 85% complementary to each other, and OH at 2 position of glycosyl of some or all of nucleotides is replaced by fluorine or methoxy, and phosphates between at least 3 consecutive nucleotides at the end are thioated. In the structure of the RNA inhibitor, 5MVIP and 3MVIP are also comprised, such that the RNA inhibitor has specific liver targeting. The RNA inhibitor can continuously inhibit the synthesis of an HBV surface antigen (HBsAg), can promote the production of HBV surface antibody (HBsAb), has an inhibitory effect on the most common types of HBV.

There are provided a compound having two or more phosphor moieties of which light absorption characteristics are equivalent to each other, in which the phosphor moieties adjacent to each other are each linked through a group including a structure represented by General Formula (I), and a labeled biological substance using the compound.

##STR00001## In the formula, X.sup.1 to X.sup.3 represent O, S, >NR.sup.1, or >CR.sup.2R.sup.3. R.sup.1 to R.sup.3 represent a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an acyl group, NR.sup.8R.sup.9, OR.sup.10, or an anionic group. R.sup.1 to R.sup.10 represent a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an acyl group, an aryl group, a heteroaryl group, or an anionic group. n is an integer of 2 or more. * represents a bonding site.

Provided herein are aptamers and pharmaceutical compositions comprising the same. In some embodiments, the aptamer selectively binds a protein of interest such as an extracellular receptor protein of interest (e.g., a cancer cell extracellular receptor protein, which may be differentially expressed in some embodiments). In some embodiments, the aptamer is directly linked by covalent bonding (e.g., via a geminal diamine linkage) to from 2 to 10 toxin compounds. Also provided herein is a method of selecting an aptamer that specifically binds to a protein expressed by a cell of interest, wherein in some embodiments the aptamer comprises at least one binding site for one or more active compounds. In some embodiments, primer regions flanking the variable region of the aptamers in the pool contains from 1 to 10 mismatches with respect to said forward or reverse primer.