br Introduction In the treatment of patients

Introduction In the treatment of patients with AIDS and human immunodeficiency virus type 1 (HIV-1), anti-retroviral therapy (ART), which uses anti-HIV drugs such as protease inhibitors, integrase inhibitors and reverse transferase inhibitors, has made a major contribution. There are still some serious problems however regarding side effects, emergence of resistant viruses and high costs. To overcome these problems, the development of novel drugs and an increase of the options concerning anti-HIV drugs, are required. An important target of highly desirable HIV-1 drugs is entry of the virus into host cells. The first step of this viral entry is the interaction between a viral envelope glycoprotein, gp120 and the host cell surface protein CD4. This interaction triggers conformational changes in gp120 exposing variable loops and enabling the subsequent binding of gp120 to a co-receptor, either CCR5 or CXCR4.3, 4 Small molecule CD4 mimics such as N1-(4-chlorophenyl)-N2-(2,2,6,6-tetramethylpiperidin-4-yl)oxalamide (NBD-556), which have attracted attention as HIV-1 entry inhibitors (Fig. 1). Furthermore, the interaction of CD4 mimics with the conserved “Phe43 cavity” on gp120 induces a conformational change in gp120 and causes a favorable enthalpy change similar to that caused by interaction of soluble CD4 with gp120. These properties make CD4 mimics valuable not only as entry inhibitors but also as “envelop protein openers”. CD4 mimics based on NBD-556 are composed essentially of three regions: an aromatic ring, an oxalamide linker and a piperidine moiety. Our previous studies on the structure-activity relationships (SARs) of such compounds have provided insight into the modification of the piperidine moiety, suggesting that bulky DL-Dithiothreitol groups such as a cyclohexyl ring and cationic groups such as a guanidine group on its piperidine ring might contribute to the anti-HIV activity and lower cytotoxicity as was shown in the CD4 mimic YIR-821.6, 7 Our SAR studies on the aromatic ring have shown that introduction of an electron-withdrawing group at the p-position of the phenyl ring might be associated with potent anti-HIV activity, and that a CD4 mimic, containing a m-fluoro-p-chlorophenyl aromatic group and a cyclohexyl group on the piperidine ring, has highly potent anti-HIV activity, but its cytotoxicity is also relatively high. We have also discovered the relatively low cytotoxic CD4 mimic compounds YYA-021 and MTA-003, which have a p-methylphenyl group or a 1,3-benzodioxolyl group, respectively.9, 10 As such, we speculate that our earlier SAR studies leave the modification of the main structure of the aromatic ring and the oxalamide linker undecided, and we have investigated the modification of the oxalamide linker and the aromatic ring. Initially, molecules which have a constrained structure in the region containing a part of oxalamide linker and the aromatic ring of NBD-556 were designed. The X-ray crystal structure of gp120 complexed with NBD-556 (PDB: 3TGS) shows that the oxalamide linker forms a hydrogen bond with the backbone carbonyl oxygen atoms of Asn425 of the protein and that the aromatic ring forms a structure that is coplanar with a segment of the oxalamide. Accordingly, we used an indole structure to serve as a constrained substituent of the oxalamide linker that would be coplanar with an aromatic ring. In a different strategy, molecules with a glycine linker in place of the oxalamide linker were designed to investigate the effect of the introduction of a flexible linker (Fig. 1).
Results and discussion
Conclusion
Experimental
Acknowledgements This work was supported in part by the grant for Research Program on HIV/AIDS from Japan Agency for Medical Research and Development, (AMED Grant Numbers 18fk0410002h0003 and 18fk0410006h0303), and Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (JSPS KAKENHI Grant Number JP15H04652). It was also supported in part by the Platform for Drug Discovery, Informatics, and Structural Life Science of MEXT, Japan, and the Cooperative Research Project of Research Center for Biomedical Engineering. We are grateful to Prof. Yoshio Hayashi and Dr. Akihiro Taguchi, Tokyo University of Pharmacy and Life Sciences for their assistance in the molecular modeling.