SMM-chemokines: a class of unnatural synthetic molecules as chemical probes of chemokine receptor biology and leads for therapeutic development.
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.
Kumar
Santosh
S
Department of Biochemistry, University of Illinois at Urbana-Champaign, 61801, USA.
Choi
Won-Tak
WT
Dong
Chang-Zhi
CZ
Madani
Navid
N
Tian
Shaomin
S
Liu
Dongxiang
D
Wang
Youli
Y
Pesavento
James
J
Wang
Jun
J
Fan
Xuejun
X
Yuan
Jian
J
Fritzsche
Wayne R
WR
An
Jing
J
Sodroski
Joseph G
JG
Richman
Douglas D
DD
Huang
Ziwei
Z
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*
D019380:Anti-HIV Agents; D018925:Chemokines; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine