Frontiers in Clinical Drug Research: HIV

Human papillomavirus (HPV) infection is the most common sexually transmitted disease worldwide and most sexually active individuals of both sexes acquire HPV at least once during their life. This virus is associated with >90% of anal and cervical cancers. Human immunodeficiency virus (HIV) infection increases incidence of both invasive cervical cancer and anal cancer. The risk of anal HPV infection declines with age in women, whereas this is not the case in men. Prophylactic HPV vaccines represent a promise for cervical and anal cancer prevention in HIVpositive people. Still now, no data are available for prevention of HPV related cancers with anti-HPV vaccination in adult HIV-positive people, but several trials are on-going. Both vaccines are well tolerated and the adverse effects are comparable to those observed in HIV negative people. However, an implementation of secondary prevention would be useful to reduce cervical and anal cancer incidence and mortality after a much shorter interval in all infected people, even in aged subjects.

In the recent years, integrase (IN) has emerged as an important new target for the development of anti-HIV-1 agents. The enzyme is involved in a key stage of the retroviral replicative cycle, and interacts with a range of cellular co-factors. Due to the absolute necessity of the enzyme for successful infection and the range of cellular cofactors employed by the enzyme, new ways of targeting both IN and its cofactors could yield agents with improved resistance profiles. Allosteric inhibitors are currently receiving a great deal of focus from both academia and industry alike and offer the possibility of a new class of anti-HIV-1 inhibitor.

Human Immunodeficiency Virus (HIV) is a retrovirus which affects mainly the host’s immune system along with other systems. Discovered in 1983, HIV created a havoc because of its high mortality due to opportunistic infections and AIDS related carcinoma. The pandemic caused by HIV was due to its easy transmission through blood, blood products, unprotected sex, sharing of needles among intravenous drug abusers and mother to foetus etc. Initially no drug or vaccine was available and the first antiretroviral drug zidovudine was approved for clinical use in 1987. Gradually different classes of antiretroviral drugs have been developed. With use of monotherapy, drug resistance in HIV developed fast due to mutation. In 1996, three studies reported that triple therapy effectively halted the replication of HIV and 60-80% reduction in HIV related deaths, illness and hospitalization, with this, the era of HAART (Highly Active Antiretroviral Therapy) began. HAART is actually Combination Antiretroviral Therapy (CART) and now has become the standard of care. Though HAART does not cure HIV, it stops HIV from replication and transmission to others. In September, 2015, Revised WHO Guidelines for global HIV treatment, has recommended the immediate initiation of ART at the time of diagnosis which has revolutionized HIV treatment. Now with HAART, the person infected with HIV can expect a normal to near normal life expectancy which is really a boon to mankind.

The human immunodeficiency virus (HIV-1) enters cells through a series of molecular interactions between the envelope protein and cellular receptors, thus providing many opportunities to block infection. HIV-1 entry inhibitors are a complex group of drugs with multiple mechanisms of action depending on the stage of the viral entry process they target. Actually, entry inhibitors fall into three categories: attachment inhibitors, co-receptor inhibitors and fusion inhibitors. Maraviroc and Enfuvirtide–that target gp120-CCR5 interaction and gp41-mediated fusion are currently being used in the clinic. Meanwhile, a wide array of additional agents are in various stages of development. The small molecule attachment inhibitor BMS-663068 has shown potent antiviral activity in early phase studies, and phase II trials are underway. The post-attachment inhibitor ibalizumab has shown antiviral activity in phase I and II trials; further studies including subcutaneous delivery of drug to healthy individuals are anticipated. Cenicriviroc, a small-molecule CCR5 antagonist that also has activity as a CCR2 antagonist, has entered phase II studies. No CXCR4 antagonists are currently in clinical trials, but next-generation injectable peptide fusion inhibitors have been ongoing with human trials. These compounds should be used in drug combination regimens to achieve the highest possible benefit, tolerability and compliance and to diminish the risk of resistance development. Unfortunately, as is the case for other classes of antiretroviral drugs that target other steps in the viral life cycle, HIV-1 can also become resistant to entry inhibitors. In this part, we will summarize the current progress in the development of different class of entry inhibitors and the facing limitations in clinical use.

Despite being the first anti-viral described to be effective against HIV, reverse transcriptase inhibitors remain the cornerstone of highly active antiretroviral therapy (HAART). There are two broad classes of reverse transcriptase inhibitor, the nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). In this part, we firstly introduce the approved reverse transcriptase inhibitors containing eight NRTIs (zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine and tenofovir disoproxil fumarate) and five NNRTIs (nevirapine, efavirenz, delavirdine, etravirine and rilpivirine). As a dNTP analog, an NRTI is converted to a dNTP analog by a phosphorylation cascade performed by cellular kinases, and then RT catalytically incorporates the drug as an NRTI monophosphate at the 3'-end of the growing viral DNA primer. Upon incorporation, an NRTI inhibits the elongation of DNA primer because NRTIs lack a 3'-OH group that prevents addition of the next nucleotide. An NRTI-triphosphate does not block the activity of an RT molecule, however, certain RT mutations cause NRTI resistance by discriminating an NRTI-triphosphate from the analogous dNTP substrate. Unlike NRTIs that do not directly inhibit RT, an NNRTI drug binds to a hydrophobic pocket in the palm sub-domain adjacent to the base of the thumb sub-domain and allosterically inhibits DNA polymerization. The NNRTI pocket permits the design of highly specific inhibitors having low toxicities and minimal side effects. The NNRTI pocket is not required to be highly conserved for carrying out the enzymatic activity unlike the conserved active site or dNTP-binding site of RT. Therefore, HIV-1 has a relatively lower genetic barrier for developing NNRTIresistance mutations than for NRTI-resistance mutations. Primary NNRTI-resistance mutations appear in and around the NNRTI pocket, that is, most of the pocket residues can mutate to confer NNRTI resistance. Then we will focus on six new drugs which are currently in preclinical or approved for second-line therapy and describe the patterns of resistance associated with their applications as well as the underlying mechanisms that have been described. Newer RTIs have greater anti-viral activity and less toxic than older. Some reverse transcriptase inhibitors with a low genetic barrier are more commonly used due to affordability and availability in resource-limited settings. While their application results in the emergence of specific patterns of antiviral resistance, useful strategies and new compounds are necessary for patients in such settings.

Since the discovery of HIV as the etiology for AIDS 30 years ago, major progress has been made, including the discovery of drugs that now control the disease. Integration of the HIV-1 DNA is required and essential to maintain the viral DNA in the infected cell. Integration process occurs in several events, mainly in endonucleolytic processing of the 3’ ends of the viral DNA and strand transfer or joining of the viral and cellular DNA. The design and discovery of integrase inhibitors were first focused on targeting the catalytic site of IN with a specific effect on strand transfer. Several integrase inhibitors were developed clinically. Here, we reviewed the integrase (IN) inhibitors from the discovery of the first compounds 20 years ago to the approval of two highly effective IN strand transfer inhibitors, raltegravir and elvitegravir, and the promising clinical activity of dolutegravir. We divide the development of integrase inhibitors into six parts, which are diketo acids, peptides, nucleotides, natural compounds and biological product, polyhydroxylated aromatic compounds and other inhibitors. After summarizing the molecular mechanism of integrase inhibitors, we discuss the remaining challenges. Those include: overcoming resistance to clinical drugs, long-term safety, cost of therapy, and the development of new classes of inhibitors.

HIV protease plays a crucial role in the viral life cycle by processing the viral Gag and Gag-Pol polyproteins into structural and functional proteins essential for viral maturation. Inhibition of HIV-1 protease leads to the production of noninfectious virus particles and hence is an important therapeutic target for antiviral therapy in AIDS patients. It is a 99-residue protein belonging to the class of aspartic acid proteases, functioning as a catalytic dimer. The inclusion of protease inhibitors (PIs) in highly active antiretroviral therapy has significantly improved clinical outcomes in HIV-1 infected patients. The first HIV-1 protease inhibitors were developed in the mid- 1990s and approved for clinical practice by 1995. So far ten such drugs have been approved for HIV treatment by the US Food and Drug Administration, including saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, fosamprenavir, atazanavir, tipranavir and darunavir, and broadly divided into first, second, and third generations. Expect for tipranavir, all of them are competitive peptidomimetic HIV protease inhibitors, which are able to mimic the transition state of HIV-1 protease substrates. However, the rapid emergence of drug-resistant HIV-1 strains and the appearance of cross-resistance are severely limiting the long-term treatment options, all of these make it urgent to develop new HIV protease inhibitors to combat the global disease. Thus, numerous efforts have been made in the design and synthesis of novel protease inhibitors with broad-spectrum activity against multidrug-resistant HIV-1 variants by medicinal chemists. Recently, considerable attention has been paid to the development of newer compounds capable of inhibiting wild-type and resistant HIV-1 protease. In this review, we have made an attempt to provide an overview on newly developing peptidomimetic and non-peptidomimetic PIs, and treatment of related recent patents in the development of novel PIs.

HIV-1 infection can be effectively controlled by highly active antiretroviral therapy (HAART), which improves the quality of lives of infected individuals, but fails to completely eradicate the virus, even after decades of treatment. This issue, together with the emergence of multi-drug-resistant viruses, clearly underscores the continuing need to find novel agents able to target vulnerable steps in the viral replication cycle. HIV transcriptional regulation is a crucial step required to re-initiate viral replication from post-integration latency after interruption of therapy and to keep the virus in circulation. In this step, the viral protein Tat plays a central role by dramatically increasing the production of elongated transcripts through its unique interaction with the viral TAR RNA and the cellular cofactor P-TEFb, together with a myriad of other host factors which are recruited to the viral promoter to ensure efficient transcription. The transcriptional machinery, involving an intricate interplay of many viral and cellular components, offers a plethora of potential therapeutic targets that have not yet been exploited by any of the antiretroviral drugs used in therapy.