[Problem to be Solved] It is intended to provide a fusion polypeptide that regulates the transcription of a target gene.

[Solution] The present inventors have provided a fusion polypeptide comprising: a cell-penetrating peptide; a DNA-binding polypeptide; and a transcriptional regulator.

The present disclosure concerns cucurbit[n]uril (CB) complexes of cucurbit[8]uril (CB[8]) and/or cucurbit[7]uril (CB[7]) that secure or host platinum conjugated terpyridines. The platinum center can further secure a protein through the thiol of a cysteine or an imidazole of a histidine therein. Additional CBs can secure the peptide through phenyl side chains. CB[8] will secure a dimer of platinum-terpyridines in a head-to-head alignment or a peptide dimer through a head-to-tail alignment. The application of multiple CBs allows for varying CB complex geometries. Also contemplated are methods of using the platinum-terpyridines to selectively bind cysteine rich proteins, such as cysteine proteases.

Compounds having drug and bio-affecting properties, their pharmaceutical compositions and methods of use are set forth. In particular, betulinic acid derivatives that possess unique antiviral activity are provided as HIV maturation inhibitors, as represented by compounds of Formula I: ##STR00001## These compounds are useful for the treatment of HIV and AIDS.

Compositions and methods for targeted treatment of cancer are disclosed. In particular, the invention relates to methods of targeting anti-cancer therapy to cells exhibiting aberrant signaling associated with cancer pathogenesis by administering synthetic signaling proteins that couple detection of an oncogenic signal to release of therapeutic agents into cancerous cells.

This application is directed generally to foot-and-mouth disease virus (FMDV) 3C proteases that have been modified by mutating a polynucleotide sequence coding for the FMDV 3C protease. The modified FMDV proteases exhibit proteolytic activity on FMDV P1 precursor protein and exhibit a reduction in one or more toxic or inhibitory properties associated with an unmodified FMDV 3C protease on a host cell used to recombinantly produce it. Vectors carrying polynucleotides encoding modified FMDV 3C protease sequences can induce production of FMDV virus-like particles in a host cell when expressed in the host cell. The modified FMDV 3C proteases can generally be used to produce immunogenic FMDV preparations capable of inducing an immune response against FMDV.

Disclosed herein include methods, compositions, and kits suitable for robust and tunable control of payload gene expression. Some embodiments provide rationally designed circuits, including miRNA-level and/or protein-level incoherent feed-forward loop circuits, that maintain the expression of a payload at an efficacious level. The circuit can comprise a promoter operably linked to a polynucleotide encoding a fusion protein comprising a payload protein, a protease, and one or more self-cleaving peptide sequences. The payload protein can comprise a degron and a cut site the protease is capable of cutting to expose the degron. The circuit can comprise a promoter operably linked to a polynucleotide comprising a payload gene, a silencer effector cassette, and one or more silencer effector binding sequences.

A method of identifying compounds that reduce main protease (Mpro) activity of a coronavirus is described, which comprises identifying compounds that bind to and stabilize a modified Mpro in an oxidized conformation with a disulfide bond formed between Cys145 (C145) and Cys117 (C117) of Mpro, reducing the catalytic activity of the modified Mpro. The modified Mpro may comprise substitution of a residue at one or both sites of His163 (H163), and/or Phe140 (F140). A modified Mpro enzyme structure (and its in vitro synthesized form) is described, together with a system for screening or designing compounds useful in treatment or prophylaxis of coronavirus infection such as infection from SARS-CoV-2.

Some embodiments of the systems, methods and compositions provided herein relate to a compound protease. In some embodiments, the compound protease includes a protease domain and a cut site for another enzyme. In some embodiments, the compound protease includes an association domain. In some embodiments, the compound protease is part of a protein circuit.

This application is directed generally to foot-and-mouth disease virus (FMDV) 3C proteases that have been modified by mutating a polynucleotide sequence coding for the FMDV 3C protease. The modified FMDV proteases exhibit proteolytic activity on FMDV P1 precursor protein and exhibit a reduction in one or more toxic or inhibitory properties associated with an unmodified FMDV 3C protease on a host cell used to recombinantly produce it. Vectors carrying polynucleotides encoding modified FMDV 3C protease sequences can induce production of FMDV virus-like particles in a host cell when expressed in the host cell. The modified FMDV 3C proteases can generally be used to produce immunogenic FMDV preparations capable of inducing an immune response against FMDV.

The invention provides methods and systems for production of recombinant protein, and particularly, for production of recombinant protein from inclusion bodies. For example, in one aspect, the method comprises providing a protein preparation comprising inclusion bodies, preparing an inclusion body dispersion, and exposing the protein preparation to high pressure in a pressure vessel, to disaggregate and refold the inclusion body protein.