The present disclosure relates to solid state forms of Voclosporin and salts thereof, processes for preparation thereof and pharmaceutical compositions thereof.

Provided are novel types of hybrid cyclic libraries that contain a known protein binding domain of a natural product. Also provided are synthetic methods to make such libraries and methods for the deconvolution of hits using partially split-pooled library compounds. Such methods are applicable for use with the entire human proteome to screen such libraries that bind and for the identification of hits.

A cyclosporin derivative which is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a viral infection:

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wherein: A represents

##STR00002## B represents methyl or ethyl, R.sub.2 represents ethyl or isopropyl, R.sub.4 represents —CH.sub.2CH(CH.sub.3)CH.sub.3, —CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3, —CH(CH.sub.3)CH.sub.3 or —CH(CH.sub.3)CH.sub.2CH.sub.3, and either (a) one of R.sub.1 and R.sub.1* represents hydrogen and the other represents methyl, and R.sub.3 represents -L.sub.3-G.sub.3, or (b) one of R.sub.1 and R.sub.1* represents hydrogen and the other represents -L.sub.1-G.sub.1, and R.sub.3 represents H, wherein L.sub.1 and L.sub.3 represent a direct bond, a C.sub.1-C.sub.6 alkylene group or a C.sub.2-C.sub.6 alkenylene group; and G.sub.1 and G.sub.3 represent a hydrogen atom, a —COOR′ group, or a phenyl moiety which is unsubstituted or substituted by one, two or three substituents selected from a halogen atom, a —COOR′ group, a —CONR′R″ group, a hydroxyl group, a C.sub.1-C.sub.6 alkyl group and a C.sub.1-C.sub.6 alkoxy group, wherein R′ and R″ are the same or different and represent hydrogen or a C.sub.1-C.sub.6 alkyl group, provided that (a) G.sub.1 does not represent a hydrogen atom when L.sub.1 represents a direct bond or methylene, and (b) G.sub.3 does not represent a hydrogen atom when L.sub.3 represents a direct bond or methylene.

The invention is directed to isomeric mixtures of cyclosporine analogs that are structurally similar to cyclosporine A. The mixtures possess enhanced efficacy and reduced toxicity over the individual isomers and over naturally occurring and other presently known cyclosporines and cyclosporine derivatives. Embodiments of the present invention are directed toward cis and trans-isomers of cyclosporin A analogs referred to as ISA.sub.TX247, and derivatives thereof. Mixtures of ISA.sub.TX247 isomers exhibit a combination of enhanced potency and reduced toxicity over the naturally occurring and presently known cyclosporins. ISA.sub.TX247 isomers and alkylated, arylated, and deuterated derivatives are synthesized by stereoselective pathways where the particular conditions of a reaction determine the degree of stereoselectivity. The ratio of isomers in a mixture comprises greater than about 80 percent by weight of the E-isomer and less than about 20 percent by weight of the Z-isomer, based on the total weight of the mixture.

The present disclosure provides methods and reagents useful for analyzing protein-protein interfaces such as interfaces between a presenter protein (e.g., a member of the FKBP family, a member of the cyclophilin family, or PIN1) and a target protein. In some embodiments, the target and/or presenter proteins are intracellular proteins. In some embodiments, the target and/or presenter proteins are mammalian proteins.

The invention is directed to a system comprising a lentivirus vector particle which encodes at least one guide RNA sequence that is complementary to a first DNA sequence in a host cell genome, a Cas9 protein, and optionally a donor nucleic acid molecule comprising a second DNA sequence. The invention also is directed to a method of altering a DNA sequence in a host cell using such a system, where the host cell can be in a human and the altered DNA can be of the human β-globin gene. The invention also is directed to a fusion protein comprising a Cas9 protein and a cyclophilin A (CypA) protein. The invention also is directed to sequences of vectors that can be used in the system and method.

The present disclosure relates to solid state forms of Voclosporin processes for preparation thereof, pharmaceutical compositions thereof and uses thereof for treating lupus nephritis.

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The invention features compounds (e.g., macrocyclic compounds) capable of modulating biological processes, for example through binding to a presenter protein (e.g., a member of the FKBP family, a member of the cyclophilin family, or PIN1) and a target protein (e.g., a eukaryotic target protein such as a mammalian target protein or a fungal target protein or a prokaryotic target protein such as a bacterial target protein). These compounds bind endogenous intracellular presenter proteins, such as the FKBPs or cyclophilins, and the resulting binary complexes selectively bind and modulate the activity of intracellular target proteins. Formation of a tripartite complex among the presenter protein, the compound, and the target protein is driven by both protein-compound and protein-protein interactions, and both are required for modulation of the targeted protein's activity. In some embodiments, the compounds of the invention “re-program” the binding of the presenter proteins to protein targets that either do not normally bind to the presenter protein (e.g., do not show detectable binding in mammalian cells absent the compound). In some embodiments, provided compounds “re-program” presenter protein binding to greatly enhance interaction with a particular target with which it may have some interaction absent the compound. Interactions achieved through such reprogramming result in an ability to modulate the activity of these new targets.

The present invention relates to a salt of a compound of formula (I) and uses thereof in medicine. Specifically, it relates to maleate of compound of formula (I) and pharmaceutically compositions thereof. Furthermore, the invention relates to the uses of maleate herein and pharmaceutically compositions thereof disclosed herein in the manufacture of a medicament, especially in the manufacture of a medicament for preventing, managing, treating or lessening hepatitis C virus (HCV) infection.

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An objective of the present invention is to provide methods of producing a cyclic organic compound using a continuous stirred tank reactor(s) (CSTR), the methods being capable of achieving excellent impurity-suppressing effects (quality improvement), reduction in reaction-tank size, continuous production, and such. The present inventors conducted studies on cyclization reactions using a CSTR(s), which had not been conventionally used for cyclization reactions for cyclic compounds. As a result, the inventors have found that the present methods can achieve excellent impurity-suppressing effects (quality improvement), reduction in reaction-tank size, continuous production, and such, as compared with conventional cyclization methods. Furthermore, the present inventors have also found that the above-mentioned improvement effects can efficiently be achieved even in the production of cyclic peptides and heterocyclic compounds by applying simulation methods that had been conventionally used mainly at the fine chemicals plant level to the cyclization reactions of the present invention, thereby experimentally predicting the reaction rate of a cyclization reaction, and setting the flow volume (residence time), the concentrations of precursor and cyclic organic compound, and the temperature for the cyclization reaction and such which affect these conditions, in the cyclization reaction using a CSTR(s).