title: SMM-chemokines: a class of unnatural synthetic molecules as chemical probes of chemokine receptor biology and leads for therapeutic development.
abstract: Chemokines and their receptors play important roles in numerous physiological and pathological processes. To develop natural chemokines into receptor probes and inhibitors of pathological processes, the lack of chemokine-receptor selectivity must be overcome. Here, we apply chemical synthesis and the concept of modular modifications to generate unnatural synthetically and modularly modified (SMM)-chemokines that have high receptor selectivity and affinity, and reduced toxicity. A proof of the concept was shown by transforming the nonselective viral macrophage inflammatory protein-II into new analogs with enhanced selectivity and potency for CXCR4 or CCR5, two principal coreceptors for human immunodeficiency virus (HIV)-1 entry. These new analogs provided insights into receptor binding and signaling mechanisms and acted as potent HIV-1 inhibitors. These results support the concept of SMM-chemokines for studying and controlling the function of other chemokine receptors.
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign, 61801, USA.
authors.forename: Santosh
authors.initials: S
authors.lastname: Kumar
authors.forename: Won-Tak
authors.initials: WT
authors.lastname: Choi
authors.forename: Chang-Zhi
authors.initials: CZ
authors.lastname: Dong
authors.forename: Navid
authors.initials: N
authors.lastname: Madani
authors.forename: Shaomin
authors.initials: S
authors.lastname: Tian
authors.forename: Dongxiang
authors.initials: D
authors.lastname: Liu
authors.forename: Youli
authors.initials: Y
authors.lastname: Wang
authors.forename: James
authors.initials: J
authors.lastname: Pesavento
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Xuejun
authors.initials: X
authors.lastname: Fan
authors.forename: Jian
authors.initials: J
authors.lastname: Yuan
authors.forename: Wayne R
authors.initials: WR
authors.lastname: Fritzsche
authors.forename: Jing
authors.initials: J
authors.lastname: An
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Sodroski
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Richman
authors.forename: Ziwei
authors.initials: Z
authors.lastname: Huang
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D002460:Cell Line; D018925:Chemokines / Q000138:chemical synthesis* / Q000145:classification / Q000494:pharmacology* / Q000633:toxicity; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D019718:Receptors, CXCR4 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism*
chemical_list: D019380:Anti-HIV Agents; D018925:Chemokines; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine