title: Small-Molecule CD4 Mimics Containing Mono-cyclohexyl Moieties as HIV Entry Inhibitors.
abstract: CD4 mimics are small molecules that inhibit the protein-protein interaction between gp120 and CD4, which is a key interaction for the entry of human immunodeficiency virus (HIV) into host immune cells. In the present study, mono-cyclohexyl-type CD4 mimics were designed to form hydrophobic and electrostatic interactions with Val430 and Asp368 located in the entrance of the Phe43 cavity of gp120, the interaction site of CD4. YIR-329, a novel 1-azaspiro[5.5]undecane derivative with a cyclohexyl ring attached to the piperidine ring, exhibited only slightly weaker anti-HIV activity than a previously described lead HAR-171, and modeling results indicated the formation of advantageous interactions by the para-chlorophenyl moiety of YIR-329. To introduce an electrostatic interaction with Asp368, derivatives with a guanidino group on the piperidine nitrogen atom were synthesized. Mono-cyclohexyl-type CD4 mimics with a guanidino group, such as YIR-819 (N(1) -(4-chlorophenyl)-N(2) -(1-(2-(N-(amidino)glycinamide)ethyl)-2-cyclohexylpiperidin-4-yl)oxalamide) and YIR-821 (1-(2-(5-guanidinovaleramide)ethyl derivative of YIR-819), were identified that exhibit approximately fivefold more potent anti-HIV activity than YIR-329. In combination with a neutralizing antibody, their anti-HIV activities were augmenting. Modeling results suggest that these compounds interact effectively with Val430 and either Asp368 or Asp474 in the gp120 Phe43 cavity. YIR-819 and YIR-821 represent useful lead compounds for the further development of HIV-1 entry inhibitors and could potentially be useful for co-administration with neutralizing antibodies for the treatment of HIV infection and AIDS.
authors.affiliation: Institute of Biomaterials & Bioengineering, Tokyo Medical & Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo, 101-0062, Japan.
authors.forename: Nami
authors.initials: N
authors.lastname: Ohashi
authors.affiliation: AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan.
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Harada
authors.affiliation: Institute of Biomaterials & Bioengineering, Tokyo Medical & Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo, 101-0062, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Mizuguchi
authors.affiliation: Institute of Biomaterials & Bioengineering, Tokyo Medical & Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo, 101-0062, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Irahara
authors.affiliation: Institute of Biomaterials & Bioengineering, Tokyo Medical & Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo, 101-0062, Japan.|Pharmaceutical Department, Keio University Hospital, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Institute of Biomaterials & Bioengineering, Tokyo Medical & Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo, 101-0062, Japan.
authors.forename: Misato
authors.initials: M
authors.lastname: Kotani
authors.affiliation: Institute of Biomaterials & Bioengineering, Tokyo Medical & Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo, 101-0062, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Nomura
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto, 860-0811, Japan.
authors.forename: Shuzo
authors.initials: S
authors.lastname: Matsushita
authors.affiliation: AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan. ykazu@nih.go.jp.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Yoshimura
authors.affiliation: Institute of Biomaterials & Bioengineering, Tokyo Medical & Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo, 101-0062, Japan. tamamura.mr@tmd.ac.jp.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tamamura
mesh_terms: D015704:CD4 Antigens / Q000737:chemistry*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015699:HIV Envelope Protein gp120 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; D054852:Small Molecule Libraries
keywords: CD4; HIV-1 entry; antiviral agents; gp120; inhibitors; protein-protein interactions