Antiviral Research, 2013, 98, 365-372.

A Novel Anti-HIV Active Integrase Inhibitor with a Favorable In Vitro Cytochrome P450 and Uridine 5′-diphospho-glucuronosyltransferase Metabolism Profile. 

Maurice O. Okello,1 Sanjay Mishra,1 Malik Nishonov,1 Marie K. Mankowski,2 Julie D. Russell,2 Jiayi Wei,2 Priscilla A. Hogan,2 Roger G. Ptak,2 and Vasu Nair1* 

1The Center for Drug Discovery and the College of Pharmacy, University of Georgia, Athens, GA 30602, USA.

 2Infectious Disease Research Department, Southern Research Institute, Frederick, MD 21701, USA

 

Abstract

Research efforts on the human immunodeficiency virus (HIV) integrase have resulted in two approved drugs. However, co-infection of HIV with Mycobacterium tuberculosis and other microbial and viral agents has introduced added complications to this pandemic, requiring favorable drug-drug interaction profiles for antiviral therapeutics targeting HIV. Cytochrome P450 (CYP) and uridine 5′-diphospho-glucuronosyltransferase (UGT) are pivotal determining factors in the occurrence of adverse drug-drug interactions. For this reason, it is important that anti-HIV agents, such as integrase inhibitors, possess favorable profiles with respect to CYP and UGT. We have discovered a novel HIV integrase inhibitor (compound 1) that exhibits low nM antiviral activity against a diverse set of HIV-1 isolates, and against HIV-2 and the simian immunodeficiency virus (SIV). Compound 1 displays low in vitro cytotoxicity and its resistance and related drug susceptibility profiles are favorable. Data from in vitro studies revealed that compound 1 was not a substrate for UGT isoforms and that it was not an inhibitor or activator of key CYP isozymes.

PMID: 23602851

 

Supplement

The retroviral enzyme, integrase, is encoded at the 3¢-end of the HIV pol gene and is essential for HIV replication.  HIV integrase facilitates the integration of viral DNA into human chromosomal DNA and this step represents the “point of no return” in HIV infection. Virus-induced helper T-cell death is suggested as being triggered by this biochemical process of integration of HIV DNA into human DNA.  For this reason, integrase represents a highly significant viral target in the discovery and development of anti-HIV therapeutic agents. Worldwide research efforts have resulted in three approved integrase drugs.  However, co-infection of HIV with other viral and microbial agents, such as TB and hepatitis B and C, among others, has introduced serious complications to this pandemic, making favorable drug-drug interaction of integrase inhibitors essential for their use in combination drug therapeutics for HIV co-infections. Profiles with respect  to phase I and phase II metabolic isozymes and isoforms of cytochrome P450 (CYP) and uridine 5′-diphospho-glucuronosyltransferase (UGT) are particularly critical in this respect.

We have discovered a highly potent HIV integrase inhibitor of the “point of no return” in HIV infectivity.  This compound exhibited significant antiviral efficacy against a large and diverse set of HIV-1 isolates, and also against HIV-2 and SIV with notably low toxicity. Its resistance and related drug susceptibility profiles were both favorable. In addition, this novel integrase inhibitor has other encouraging properties.  For example, it is not an inhibitor or activator of key CYP isozymes.  It is metabolized slowly by CYP, which provides a mechanism for its clearance.  Also, it is not a substrate for key human UGTs, which is of particular relevance, both in HIV co-infection therapeutics and in HIV treatments during fetal development and early infancy. The  antiviral efficacy of this potent anti-HIV integrase inhibitor and its drug-drug interaction and biological profile provide convincing support for its development as an anti-HIV therapeutic agent.

fig1Figure 1.  Pictorial representation of invasion of helper T-cells by HIV


fog2Figure 2.  Illustration of the specificity of binding of our integrase inhibitor (shown in green) inside the active site of the HIV-1 integrase intasome (HIV integrase-viral DNA complex, PDB code 3OYA).  The inhibitor interacts with the viral enzyme, viral DNA and two magnesium ions (shown in magenta) in the integrase active site.

 

References

  1. Okello MO, Mishra S, Nishonov M, Mankowski MK, Russell JD, Wei J,  Hogan PA, Ptak RG, Nair V 2013 A novel anti-HIV active integrase inhibitor with a favorable in vitro cytochrome P450 and uridine 5′-diphospho-glucuronosyltransferase metabolism profile. Antiviral Research 98: 365-372.
  2. Nair V, Chi, G 2007 HIV integrase inhibitors as therapeutic agents in AIDS. Reviews in Medical Virology 17:277-295.

 

Acknowledgements:

Support of this research by the National Institutes of Health (R01 AI 43181 and NCRR S10-RR025444) is gratefully acknowledged. One of us (VN) also acknowledges support from the Terry Endowment (RR10211184) and from the Georgia Research Alliance Eminent Scholar Award (GN012726). The anti-HIV data were determined by Southern Research Institute, Frederick, MD, using federal funds from the Division of AIDS, NIAID, NIH, under contract HHSN272200700041C.

fig3Contact:

Vasu Nair, Ph.D., D.Sc.

Terry Endowed Chair in Drug Discovery and GRA Eminent Scholar

Director, Center for Drug Discovery

College of Pharmacy, University of Georgia, Athens, GA 30602, USA

E-mail: vnair@rx.uga.eduvnair@uga.edu

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