BSP :: Infectious Disorders - Drug Targets Home Page

Contents

Editorial
Robert C. Goldman
[Editorial In PDF]

Multi-targeting the Entrance Door to Block HIV-1 Pp.3-15
G. Borkow and A. Lapidot
[Abstract] [Full text article]

Orthopoxvirus Targets for the Development of Antiviral Therapies Pp.17-28
Mark N. Prichard and Earl R. Kern
[Abstract] [Full text article]

Advances on Cyclin-dependent Kinases (CDKs) as Novel Targets for Antiviral Drugs Pp.29-37
L. M. Schang
[Abstract] [Full text article]

PDF Inhibitors: An Emerging Class of Antibacterial Drugs Pp.39-52
K.W. Johnson, D. Lofland, and H.E. Moser
[Abstract] [Full text article]

Amino Acid Metabolic Routes in Trypanosoma cruzi: Possible Therapeutic Targets Against Chagas’ Disease Pp.53-64
Ariel Mariano Silber, Walter Colli, Henning Ulrich, Maria Julia Manso Alves, Claudio Alejandro Pereira
[Abstract] [Full text article]

Blood-brain Barrier Drug Discovery for Central Nervous System Infections Pp.65-72
Ambrose Jong and Sheng-He Huang
[Abstract] [Full text article]

Abstracts

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Editorial
Robert C. Goldman
[Editorial In PDF]

Current Drug Targets-Infectious Disorders (CDT-ID) was launched in May of 2001 and is now starting its fifth year with the March 2005 issue. Our Special Topics issues, organized by a Guest Editor, are published twice a year and have been very well received since their inception in 2001. Two Special Topics issues are scheduled for 2005: 1) Dr. Julia Hurwitz (Department of Immunology, St. Jude Children's Research Hospital) will be the Guest Editor for our June 2005 Special Topics issue on HIV Vaccine Discovery and Development; and 2) Drs. Raffaele De Francesco and Giovanni Migliaccio (the IRBM, Merck Research Laboratories) will be the Guest Editors of our December 2005 Special Topics issue on HCV Drug Discovery and Development.

This March 2005 issue includes timely topics in the antiviral and antibacterial areas, as well as a review of novel approaches to developing new agents against Chagas’ disease, and a review focusing on the role of the blood-brain barrier in the discovery of drugs for the treatment of central nervous system infections:

Multi-targeting the Entrance Door to Block HIV-1 (G. Borkow and A. Lapidot) Multiple steps occur during HIV-1 entry, providing the opportunity for multisite targeting of the process of viral entry. Synergistic inhibition of HIV-1 proliferation can occur in in vitro using combinations of entry inhibitors that interact at different steps in the entry process. Multi-targeting may also limit the selection of resistant isolates. The possible development of compounds that target multiple steps in the entry process is discussed.

Orthopoxvirus Targets for the Development of Antiviral Therapies (M. N. Prichard and E. R. Kern) Orthopoxviruses are the causative agent of many diseases, including smallpox and monkeypox; however, current therapies are not adequate to manage out breaks of these diseases. The potential use of smallpox virus as a bioterrorism agent further underscores the need for new therapeutic agents. This review bases the framework for anti-orthopoxvirus discovery on successes with other viruses and antiviral targets, with a key focus on orthopoxvirus replication.

Advances on Cyclin-dependent Kinases (CDKs) as Novel Targets for Antiviral Drugs (L M. Schang) Many viruses rely on key cellular proteins for critical replication functions and such cell factors may equate to new antiviral targets with a broader spectrum and less likelihood for the selection of resistance. This review focuses on cellular cyclin-dependent kinases (CDKs) that are required for virus replication. Surprisingly, specific CDK inhibitors showing minimal toxicity, and some (roscovitine and flavopiridol) possess antiviral activity. Clinical trials with such agents may initiate this year.

PDF Inhibitors: An Emerging Class of Antibacterial Drugs (K.W. Johnson, D. Lofland, and H.E. Moser) We are on the verge of witnessing the introduction of another new class of antibacterial agent, one that targets the metalloenzyme peptide deformylase (PDF). Peptide analogs containing either a hydroxamate or formyl-hydroxylamine as the metal interacting group are being developed with broad spectrum antibacterial activity. Lead compounds have good pharmacokinetic properties and efficacy in animal models of bacterial infection, and selected compounds have entered into clinical trials.

Amino Acid Metabolic Routes in Trypanosoma cruzi: Possible Therapeutic Targets Against Chagas’ Disease (A. Silber, W. Colli, H. Ulrich, M. J. M. Alves and C A. Pereira) Ten to twenty million persons are infected with Trypanosoma cruzi worldwide; however, only two drugs are currently available for treatment, both with significant side effects and suboptimal efficacy. This review focuses on amino acid metabolism during the complex life cycle of the parasite and identifies possible targets involved in storing energy, adapting to stress, and regulating parasite differentiation within the host.

Blood-brain Barrier Drug Discovery for Central Nervous System Infections (A. Jong and S-H. Huang) Antibiotics must pass through the blood-brain barrier (BBB) in order to be maximally effective in the treatment of central nervous system (CNS) infection. This review addresses the question: “How can the chemistry and biology of the BBB, and infectomics be exploited for the development of drugs against CNS infections?” Key strategies addressed are physiochemical approaches, biochemical approaches (based on drug efflux and receptor mediated transport), and mechanisms of neuronal damage.

Infectious disease in the twenty-first century: The topics below are not meant to be an exhaustive or even expert opinion, but rather a rapid fire targeting of some recent and some older events related to national and global infectious disease. My apologies if by alacrity I have misrepresented any of the original source or contributor’s work or conclusions. If you do not have enough stress is your life, read on. Here are some frightening statistics and events that push home the fact that even without attack with an agent of bioterrorism, the spread of infectious disease due to natural causes and inattention to sound world health policies can lead to devastating, yet for the most part preventable, morbidity and mortality on a global scale.

Polio: Since 1988 the number of cases of polio worldwide was reduced from 350,000 to 784 in 2003. Eradication of polio is an achievable goal, set for December 31, 2005 by the WHO. However, adopting unsound health care policies can derail the best made plans. Cases of polio increased from 784 (2003) to 1185 (2004) mainly due to a vaccine boycott in Nigeria. The virus then spread to unvaccinated persons in neighboring polio free countries in Africa and beyond. Adding to this problem is the political turmoil in several African countries that hampers current control efforts.

Transmission of tuberculosis in normal venues: In spite of lingering ‘folk tales’ such as catching a cold if you don’t wear your slippers on a cold morning (my mother vehemently enforced this rule, which lead to my first search for germs on my bedroom floor), the average person is likely to be aware that catching something infectious usually occurs by being in close proximity to an ‘infectious’ person.

However, nothing is better than real-life studies to drive the message home, e.g. Kline S.E., Hedemark L.L., Davies S.F. Outbreak of tuberculosis among regular patrons of a neighborhood bar. N. Engl. J. Med.1995; 333 (4): 222-227. The social setting is a neighborhood bar frequented by a homeless patron who happens to have active pulmonary tuberculosis. The result: transmission of tuberculosis to 41 of 97 other patrons/staff of the establishment. That’s a hefty 42% transmission rate, with a rapid 34% rate of progression to active disease among those infected.

Being a microbiologist by training I get very nervous on an airline flight when someone starts coughing and sneezing. I even hold my breath for several seconds after being interrupted by a nearby coughing spree, hoping that I won’t inhale the infectious germs. After reading the report by Kenyon T.A., Valwa, S.E., Ihle W.W., Onorato I.M., and Castro K.G. (Transmission of multi-drug-resistant Mycobacterium tuberculosis during a long airplane flight. N. Engl. J. Med. 1996; 334: 933-938), holding my breath did not seem so silly. This report documents person to person transmission of multi-drug resistant tuberculosis during long airline flights.

A traveler with active multi-drug resistant tuberculosis travels on a long flight. The result: of the 1042 passengers and crew there was strong evidence of transmission of tuberculosis to 6 passengers located in the same cabin with the infected person. Although based on a rather sparse data set, statistics indicate that during the mid-90’s thirty passengers with tuberculosis may have traveled along with 9 million other passengers. A more likely estimate was that 1 in 26000 passengers may have been exposed. Although the overall rate of transmission is low, the rate increases dramatically when the infected person is actively infected with highly transmissible tuberculosis, and when the uninfected person is within close proximity on longer flights. Up to one third of the world’s population is infected with tuberculosis and 8 million persons develop active disease each year. Two to three million die each year. Overall estimates are that each active disease case comes into close contact with up to nine persons and transmits the disease to three of the nine. Only very simple mathematical skills are needed to correctly interpret the magnitude of the problem.

More sophisticated analysis can offer in depth understanding of this major global health problem, and offer projections for the future to assist in developing the best control strategies. S. Blower and T. Chou: [Nature Medicine 10 (10) 1111 (2004)] examine the possible outcomes for the future of global tuberculosis and for ‘hot zones’, defined as > 5% prevalence or incidence of multidrug resistant tuberculosis (MDR; minimally resistant to isoniazid and rifampcins). Given the current state of affairs with tuberculosis control programs, the scenarios tested gave the probability of eradicating tuberculosis as 1/100, the likelihood that post-MDR strains will out-compete other strains as 13/100, and the chance for co-existence of pan-sensitive strains with strains in various stages of progression to MDR, and fully MDR strains, as 86/100. New hot zones will arise where a high rate of MDR tuberculosis takes a dramatic toll on health care resources. During the mid-1990s an outbreak of MDR tuberculosis in New York City was estimated to cost upwards of $1 billion to control ($250,000 per patient) and sent a wake up call to the national health care policy for tuberculosis control.

T. Cohen and M. Murray [Nature Medicine 10 (10) 1117 (2004)] modeled the fate of MDR tuberculosis as a function of strain fitness. Even in the background of moderate to good tuberculosis control programs and suboptimal fitness of MDR strains, models predict that initial populations of ‘fit’ MDR strains may evolve and eventually out-compete pan-sensitive strains. Most impressing, and disturbing, was modeling that was carried out for the 350 year period post the introduction of modern control measures (i.e. limiting exposure and drug treatments developed in the 1920’s to 1950’s). Worst case scenarios projected areas where up to 60% of the population is infected (latently) with MDR stains, 600/100,000 as a rate for infectious persons carrying MDR strains, and the evolution of circulating MDR strains that are even more fit than their weaken parental strains.

Add to this the complex and devastating interaction of HIV infection with tuberculosis and one can easily see why infectious disease specialists are particularly concerned about the future of global health. Then add an uncontrolled increase in HIV/AIDS, a possible new influenza pandemic with avian flu recombinants that gain the ability to transmit efficiently from man to man, shortages of vaccine production, a new SARS outbreak, a monkeypox outbreak, a smallpox bioterrorism attack, or a new emerging virus. Perhaps as a species we should better unite in defensive and offensive strategies against our true enemies, the willful but mindless microbes that we have been battling since the dawn of man. Thanks to the great microbiologist of the past (Hooke, van Leeuwenhoek Lister, Ehrlich, Pasteur, Koch, Jenner, Sydenham, Domagk, Wakesman, Fleming) we were able to make enormous advances in managing infectious disease. Unfortunately the war is not over and there will be many new battles to face.

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Multi-targeting the Entrance Door to Block HIV-1
G. Borkow and A. Lapidot
[Full text article]

The multistep nature of HIV-1 entry provides multisite targeting at the entrance door of HIV-1 to cells. Blocking HIV-1 entry to its host cells has clear advantages over blocking subsequent stages in the life cycle of the virus. Indeed, potent cooperative and synergistic inhibition of HIV-1 proliferation has been observed in in vitro studies with several entry inhibitor combinations, interacting with different steps of the HIV-1-cell entry cascade. Targeting a compound to several steps of the viral-cell entry and also to subsequent steps in the viral life cycle promises an even more effective therapeutic, by reducing the probability of HIV-1 to develop resistance. Using one drug that can target multiple sites and/or steps in the viral life cycle will have obvious advantages in clinical use. In this article we review the multistep process of HIV-1 cell entry and the current repertoire of inhibitors of this critical stage in the viral life cycle, and introduce an example of multisite HIV-1 targeting of the cell entry and subsequent critical steps in the viral life cycle.

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Orthopoxvirus Targets for the Development of Antiviral Therapies
Mark N. Prichard and Earl R. Kern
[Full text article]

The potential use of smallpox virus as a bioterror agent and the endemic presence of monkeypox virus in Africa underscores the need for better therapies for orthopoxvirus infections. The only existing clinical experience treating vaccinia and smallpox infections has been with Marboran, which suggested that antiviral therapies could be effective in treating and preventing smallpox infections, but this compound has not been pursued. Drugs that have been approved for other indications, like cidofovir, could be approved for the treatment of orthopoxvirus infections in a timely manner, and this compound has already been approved for emergency treatment of smallpox and complications from vaccination. Its lack of activity when given orally, however, limits its use in a major outbreak involving large numbers of people exposed to the virus. The discovery and development of new therapies can be achieved more rapidly by drawing on the experience and successes with other antiviral agents, particularly with the herpesviruses. This review will discuss the orthopoxvirus replication cycle in detail noting specific viral functions and their associated gene products that have the potential to serve as new targets for drug design and development. This discussion is designed to help investigators relate these targets to parallel functions and existing assays in other virus systems that have been used successfully in drug development. The rapid progress that has been achieved in recent years should yield new drugs for the treatment of these infections and might also reveal new strategies for antiviral therapy with other viruses.

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Advances on Cyclin-dependent Kinases (CDKs) as Novel Targets for Antiviral Drugs
L. M. Schang
[Full text article]

Although targeting viral proteins has lead to many successful antiviral drugs, these antivirals have certain limitations. They rapidly select for resistance, tend to be active against only a few related viruses and the proteins of a pathogen must be characterized before such drugs can be developed. Consequently, a long period is required from the identification of a new pathogen to the development of relevant antivirals, a major concern for emerging diseases. Cellular proteins are now considered as potential targets for antivirals. Drugs that target cellular proteins required for several viral functions might not easily select for drug-resistance. They may also be active against a variety of unrelated viruses, which commonly require the same cellular proteins, and against viral strains resistant to conventional antiviral drugs. These antivirals could be promptly tested against emerging viruses because even distantly related viruses commonly require the same cellular proteins.

Cellular cyclin-dependent kinases (CDKs) are required for replication of many viruses and specific pharmacological CDK inhibitors (PCIs) are proving to have surprisingly few negative side effects in clinical trials (against cancer). PCIs inhibit replication of wild-type and multi-drug resistant strains of HIV, HSV-1, HSV-2, HCMV, EBV and VZV. Two PCIs, roscovitine and flavopiridol, were recently proven active in a mouse model of HIV-induced nephropathy. Because the antiviral mechanisms of PCIs require no viral proteins, mutations in viral genes may not easily overcome inhibition by these drugs. In fact, no PCI-resistant viral mutant has been reported. PCIs are scheduled to enter clinical trials as antivirals in 2005.

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PDF Inhibitors: An Emerging Class of Antibacterial Drugs
K.W. Johnson, D. Lofland and H.E. Moser
[Full text article]

The metalloenzyme peptide deformylase (PDF) represents one of the most promising bacterial targets in the search for novel mode of action antibiotics that lack cross-resistance to existing drugs. Initial research and clinical development has focused on anti-pneumococcal applications. During optimization, peptide analogs were developed containing either a hydroxamate or formyl-hydroxylamine as metal interacting group, yielding inhibitors with in vitro activity against a broad spectrum of organisms. Preclinical studies revealed potent antibacterial activity in vivo that is paired with good pharmacokinetic properties and excellent tolerability in different species. BB-83698, a potent PDF inhibitor with i.v. and oral efficacy in preclinical animal models, represents the first class-representative compound evaluated in man. The inhibitor was administered by i.v. infusion and was shown to exhibit generally dose-proportional pharmacokinetics. It was well tolerated up to doses providing predicted therapeutic exposures. These human results, combined with the preclinical information, clearly support the potential of PDF inhibitors for development as a novel class of antibacterial therapeutics.

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Amino Acid Metabolic Routes in Trypanosoma cruzi: Possible Therapeutic Targets Against Chagas’ Disease
Ariel Mariano Silber, Walter Colli, Henning Ulrich, Maria Julia Manso Alves and Claudio Alejandro Pereira
[Full text article]

Chagas´ disease is a zoonosis caused by the parasite Trypanosoma cruzi, a haematic protozoan, transmitted by insects from the Reduviidae family. This constitutes a relevant health and socio-economic problem in the Americas, with 11 – 18 million people infected, and approximately 100 million people at risk. The therapeutic possibilities rely into two drugs, nifurtimox^® and benznidazole^®, that were discovered more than thirty years ago, and are mainly successful during the acute phase of the disease. In the majority of the cases the disease is diagnosed in the chronic phase, when the therapy is inefficient and the probability of cure is low. In addition, these drugs are highly toxic, with systemic side effects on patients.

Trypanosoma cruzi has a metabolism largely based on the consumption of amino acids, mainly proline, aspartate and glutamate, which constitute the main carbon and energy sources in the insect stage of the parasite life cycle. These amino acids also participate in the differentiation process of the replicative non-infective form (epimastigote) to the nonreplicative infective form (trypomastigote). In particular, the participation of proline in the intracellular differentiation cycle, which occurs in the mammalian host, was recently demonstrated. In addition, an arginine kinase has been described in T. cruzi and T. brucei, which converts free arginine to phosphoarginine, a phosphagen with a role as an energy reservoir. Arginine kinase seems to be an essential component of energy management during stress conditions. Taken together, these data indicate that amino acid metabolism may provide multiple as yet unexplored targets for therapeutic drugs.

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Blood-brain Barrier Drug Discovery for Central Nervous System Infections
Ambrose Jong and Sheng-He Huang
[Full text article]

Central nervous system (CNS) infections are formidable diseases with high rates of morbidity and mortality. Since the majority of antimicrobial agents discovered so far do not cross the blood-brain barrier (BBB), the treatment of CNS infections is a major challenge issue. The development of drugs to treat those diseases requires consideration of achievable brain concentrations by targeting the following question. How can the chemistry and biology of the BBB, and infectomics be exploited for the development of drugs against CNS infections? To date drug targeting approaches, such as chemistry-based, biology-based, and infectomics-based, have been implicated in the development of drugs for treatment of CNS infections. The chemistry-based strategies rely on lipid-mediated BBB drug transport as substances that readily permeate the BBB. These usually include small molecular weight of lipophilic or hydrophobic molecules. The biologybased strategies depend on endogenous BBB transport systems, including carrier-mediated transport (CMT), active efflux transport (AET), and receptor-mediated transport (RMT). These transporters play important roles in the influxes and/or effluxes of drugs including antimicrobial agents in brain capillary endothelial cells that form the BBB. Both microbial and host signatures of infectomes, which can be dissected by infectomics, provide invaluable fountains in the search for novel antimicrobial therapies. Key markers associated with the mechanisms of neuronal injury may be identified, and thus, provide important targets for the prevention and treatment of CNS infections. This review focuses on the major BBB drug targeting strategies in the development of therapeutics for CNS infections. A combination of these strategies will ultimately lead to improved treatments.