Design and Synthesis of HIV-1 Protease Inhibitors
Pp. 1-33 (33)
Sesha S. Alluri and Ashit K. Ganguly
Human immunodeficiency virus (HIV-1) protease inhibitors play an
important role as a part of the HAART (Highly Active Antiretroviral Therapy)
treatment regimen for AIDS infection. The main cellular target for HIV-1 is helper Tlymphocytes
that is critical to the immune system and renders individuals susceptible
to opportunistic infections and tumors. According to World Health Organization,
globally 36.9 million people are living with HIV-1 at the end of 2017 making HIV-1 a
prime target for drug discovery.
HIV-1 belongs to the family ‘retroviridae’ that characteristically carry their genetic
information in the form of ribonucleic acid (RNA). There are several drug targets that
interfere with the life cycle of HIV-1 virus. Drugs such as enfuvirtide inhibit the entry
of HIV-1 into the cell by interacting with CD4 receptors and co-receptors
CCR5/CXCR4. Three key enzymes involved in the survival and replication of virus
inside the host cell are reverse transcriptase, integrase, and protease. Once inside the
host, the viral enzyme reverse transcriptase converts the viral RNA into proviral DNA.
Azido thymidine (AZT) was the first reverse transcriptase inhibitor discovered. In the
next step of viral replication, the proviral DNA is inserted into the host cell genome by
the viral enzyme, HIV-1 integrase. Integrase inhibitors (e.g. raltegravir) block this step.
Following integration, viral transcription factors cause the normal cellular machinery to
produce multiple copies of viral m-RNA, which is transported from the nucleus back
into the cytoplasm. In the cytoplasm, viral core proteins are produced as long chain
polypeptides that are cleaved by the viral HIV-1 protease enzyme, into smaller
polypeptides in order to become functional. HIV-1 protease inhibitors block this step
and are considered as major breakthrough in AIDS research. Although there are several
drug classes that inhibit the life cycle of HIV-1 virus at various stages, the major
emphasis of this chapter will be on the discovery of linear sulfonamides such as
darunavir which in particular is being very successfully used in the clinic. We shall also
summarize the discovery from our laboratory of a novel class of cyclic sulfonamides as
potent HIV-1 protease inhibitors.
The HIV-1 protease inhibitors represent one of the classic examples of structure-based
drug design. The X-ray crystal structure of HIV-1 protease was determined in 1989 and
several inhibitors were soon developed based on the configuration of the active site.
Protease inhibitors such as saquinavir, ritonavir, indinavir, amprenavir, tipranavir,
darunavir etc., are successfully used for the treatment of AIDS patients. Today, new
protease inhibitors are continuously being developed and designed because HIV-1
virus mutates quickly, and current medications are becoming increasingly ineffective.
In our published work, we have successfully discovered a novel class of HIV-1
protease inhibitors based on a cyclic sulfonamide core structure. HIV-1 protease
inhibitors in clinical use such as amprenavir, tipranavir and darunavir possess
sulfonamide moiety in their core structure. Unlike open chain sulfonamides used in the
clinic, our compounds possess a conformationally restricted sulfonamide
pharmacophore. Molecular modeling was used for the design of these inhibitors and the
crucial step in their synthesis involved an unusual endo radical cyclization process.
Several analogs were synthesized in order to determine their structure activity
relationship. X-ray crystallographic analysis confirmed the binding modes of our
inhibitors to the HIV-1 protease enzyme. The structures of the novel inhibitors were
further optimized to the picomolar affinities in the HIV-1 protease assay. More work
remains to be done to determine whether these cyclic sulfonamides could be clinically
AIDS, Carbamates, Classes of HIV-1 Drugs, Cyclic Sulfonamides,
HIV-1 Protease Inhibitors, Hydrogen Bonding, Hydrophobic Interactions, HIV-1
Protease Assay, Radical Cyclisation, X-ray Crystallography.
Stevens Institute of Technology, 1 Castle Point Terrace, Hoboken, NJ-07030, USA.