Methods of generating conditionally active proteins that target senescent cells and which are conditionally active in an extracellular environment of a senescent cell. The methods include discovery methods using libraries of evolved proteins and assays employing physiological concentrations of components of bodily fluids. Also disclosed are conditionally active proteins for killing or removing senescent cells, pharmaceutical compositions employing these conditionally active proteins and methods for treatment of age-related diseases, conditions or disorders using same. The conditionally active proteins may be further evolved, conjugated to other molecules, masked, reduced in activity by attaching a cleavable moiety.

A method for preparing a cyclopeptide and a cyclopeptide preparing by the method are disclosed. The method includes the following steps: (A) providing compounds represented by the following formulas (I-1) and (I-2):

##STR00001## wherein, G, R.sub.a, R.sub.b, R.sub.c, R.sub.d, and R.sub.e are defined in the specification; (B) performing a reaction between the compounds of formulas (I-1) and (I-2) to obtain a compound represented by the following formula (I-3):

##STR00002##

and (C) performing a cyclization reaction of the compound of formula (I-3) with a catalyst of formula (II) and deprotection to obtain a compound represented by the following formula (III):

##STR00003## wherein, G′, Q, M, L.sup.1, L.sup.2, m, y, and z are defined in the specification.

A method for preparing a cyclopeptide and a cyclopeptide preparing by the method are disclosed. The method includes the following steps: (A) providing compounds represented by the following formulas (I-1) and (I-2):

##STR00001## wherein, G, R.sub.a, R.sub.b, R.sub.c, R.sub.d, and R.sub.e are defined in the specification; (B) performing a reaction between the compounds of formulas (I-1) and (I-2) to obtain a compound represented by the following formula (I-3):

##STR00002##

and (C) performing a cyclization reaction of the compound of formula (I-3) with a catalyst of formula (II) and deprotection to obtain a compound represented by the following formula (III):

##STR00003## wherein, G′, Q, M, L.sup.1, L.sup.2, m, y, and z are defined in the specification.

The disclosure relates to inhibitors of PCSK9 useful in the treatment of cholesterol lipid metabolism, and other diseases in which PCSK9 plays a role, having the Formula (I):

##STR00001##

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, N-oxide, or tautomer thereof, wherein R.sub.1, R.sub.1, R.sub.1, R.sub.1, R.sub.1, R.sub.1, R.sub.1, R.sub.1, R.sub.1, X.sub.1, X.sub.2, and X.sub.3 are described herein.

A new use of a cyclo histidine-proline (Cyclo His-Pro, CHP) is disclosed. A composition including cyclo histidine-proline (CHP) as an active ingredient has an excellent protective effect to protect kidney and liver cells from damage and/or toxicity induced by various causes. The composition is useful and effective in protecting kidney and/or liver cells/tissues and in treating a subject with kidney and/or liver diseases and/or damages.

A new use of a cyclo histidine-proline (Cyclo His-Pro, CHP) is disclosed. A composition including cyclo histidine-proline (CHP) as an active ingredient has an excellent protective effect to protect kidney and liver cells from damage and/or toxicity induced by various causes. The composition is useful and effective in protecting kidney and/or liver cells/tissues and in treating a subject with kidney and/or liver diseases and/or damages.

The invention relates to macrocyclic peptides and pharmaceutical compositions thereof. The invention further provides macrocyclic tetrapeptides comprising sarcosine. The invention further relates to pharmaceutical compositions for modulating opioid receptor activity. The macrocyclic tetrapeptides provided herein are useful in treating diseases or disorders relating to the activity of one or more opioid receptors, such as neurological disorders.

Disclosed herein is a cyclic peptide polymer. R.sup.1, R.sup.2, and R.sup.3 are organic groups. Each R.sup.4 is a covalent bond, methylene, ethylene, n-propylene, or n-butylene. Each X is —NH—, —O—, or —O—CO—. The values m and n are nonnegative integers having a sum of at least 1. The value p is an integer greater than 1. The cyclic peptide polymer may be made by providing a first cyclic peptide monomer having a protecting group on the X group, covalently binding the —CO—OH group of the first cyclic peptide monomer to a solid support having a carboxylic acid-reactive group, converting the protecting group to —XH, reacting the —XH group with the —CO—OH group of an additional cyclic peptide monomer, optionally repeating the converting and reacting steps with further additional cyclic peptide monomers, and cleaving the cyclic peptide polymer from the solid support.

##STR00001##

Disclosed herein is a cyclic peptide polymer. R.sup.1, R.sup.2, and R.sup.3 are organic groups. Each R.sup.4 is a covalent bond, methylene, ethylene, n-propylene, or n-butylene. Each X is —NH—, —O—, or —O—CO—. The values m and n are nonnegative integers having a sum of at least 1. The value p is an integer greater than 1. The cyclic peptide polymer may be made by providing a first cyclic peptide monomer having a protecting group on the X group, covalently binding the —CO—OH group of the first cyclic peptide monomer to a solid support having a carboxylic acid-reactive group, converting the protecting group to —XH, reacting the —XH group with the —CO—OH group of an additional cyclic peptide monomer, optionally repeating the converting and reacting steps with further additional cyclic peptide monomers, and cleaving the cyclic peptide polymer from the solid support.

##STR00001##

Methods for enhancing the immune response and/or treatment of diseases such as cancer comprising an agent that specifically binds TIGIT are disclosed. The TIGIT-binding agents may include polypeptides, antibodies, and/or bispecific agents.