| Current
Pharmaceutical Design
ISSN: 1381-6128 - Volume 12, 36 Issues, 2006
Current Pharmaceutical Design
Volume 11, Number 29, 2005
Contents
Novel Approaches in Designing Anti-HIV Microbicides
and Anti-HIV Agents
Executive Editor: Keykavous Parang
Editorial Pp.3729
Microbicides for Prevention of Transmission of Sexually
Transmitted Diseases Pp.3731
M.K. Howett and J.P. Kuhl
[Abstract]
Anti-HIV-1 Microbicides – ‘Chemical
Condoms’ Designed to Limit the Scourge of the HIV-1
Pandemic Pp.3747
S.J. Scholand, J.A. DeSimone and R.J. Pomerantz
[Abstract]
Toward a Design of Affordable, Topical Microbicides:
Acylcarnitine Analogues Pp.3757
R.D. Gandour
[Abstract]
Preclinical Studies of Alkylureas as Anti
HIV Contraceptive and Non-Contraceptive Vaginal Microbicides
Pp.3769
A. Rubinstein
[Abstract]
Indolyl Aryl Sulfones (IASs): Development of Highly
Potent NNRTIs Active Against wt-HIV-1 and Clinically Relevant
Drug Resistant Mutants Pp.3100
R. Silvestri and M. Artico
[Abstract]
General Articles
Ubiquitin-Proteasome Pathway Components as Therapeutic
Targets for CNS Maladies Pp.3807
S.C. Upadhya and A.N. Hegde
[Abstract]
Drug Tissue Distribution: Study Methods
and Therapeutic Implications Pp.3829
J.M. Lanao and M.A. Fraile
[Abstract]
The Antiviral Activity, Mechanism of Action,
Clinical Significance and Resistance of Abacavir in the Treatment
of Pediatric AIDS Pp.3847
J. Melroy and V. Nair
[Abstract]
Abstracts
[Back to top]
Editorial
The field of developing topical microbicides as preventive
agents against HIV is rapidly emerging. This issue of anti-HIV
drug design focuses on introducing novel approaches in designing
anti-HIV microbicides. The selection of this topic was made
with the intention to complement the first two issues of anti-HIV
Drug Design (Current Pharmaceutical Sciences, 2002,
Volume 8, number 8) and (Current Pharmaceutical Sciences,
2003, Volume 9, number 22). Additionally several
strategies in designing non-nucleoside reverse transcriptase
inhibitors (NNRTIs) that can have applications as microbicides
are discussed in the last review article.
Microbicides are anti-infective prophylactic agents formulated
for topical self-administration prior to intercourse to protect
against sexually transmitted pathogens such as HIV-1. The
article by Mary K. Howett and Jeffrey P. Kuhl summarizes the
concept and ideal design of microbicides, principles of microbicide
mechanisms, and major types of microbicides such as nonoxynol
9, antibodies and monoclonal antibodies, peptides, high molecular
weight charged polymers, entry and fusion inhibitors, and
alkyl sulfates.
The review by Pomerantz and his colleagues summarizes some
of the important products such as BufferGel, Acidform, nonoxynol
9, sodium lauryl sulfate, sodium dodecyl sulfate, C31G, sulfate
esters of polysaccacharides, Carrageenan, PRO-2000, cellulose
acetate phthalate, dendrimers, proteins, and NNRTIs, currently
in developments stages as HIV microbicides.
Amphiphiles are surfactant agents that have been investigated
as microbicides due to their broad-spectrum of activity and
fast-acting effect, but they disrupt cell membranes such as
epithelial cells and normal vagina flora. The review by Richard
D. Gandour discusses amphiphilic acylcarnitine analogues such
as Z-14 and Z-15 that may
have applications as non-irritating topical microbicides.
Alkylureas have been introduced as protein denaturing agents
that irreversibly disrupt free and intracellular HIV-1 with
a wide margin of safety. These compounds are also spermicidal
above their virucidal concentration without mucosal toxicity.
The review by Arye Rubinstein discusses the anti-HIV 1 properties
of alkylureas, their effect on peripheral blood mononuclear
cells and epithelial cell viability, mechanism of action,
and their toxicological studies
Indolyl aryl sulfones (IASs) have been introduced as potent
non-nucleoside reverse transcriptase inhibitors against wt
HIV-1 and resistant mutants. In a comprehensive review, Dr.
Silvestri and his colleague discuss the latest developments
in designing novel IASs.
I would like to thank all of the authors for their valuable
contributions to this issue. Without their dedication, the
publication of this issue would not have been possible.
References
[1] Howett, M. K., Kuhl, J. P. Microbicides for Prevention
of Transmission of Sexually Transmitted Diseases. Curr Pharm
Design 2005; 11(29): 3731-3746.
[2] Scholand, S. J., DeSimone, J. A., Pomerantz, R. J. Anti-HIV-1
Microbicides – ‘Chemical Condoms’ Designed
to Limit the Scourge of the HIV-1 Pandemic. Curr Pharm Design
2005; 11(29): 3747-3756.
[3] Gandour, R. A. Toward a Design of Affordable, Topical
Microbicide: Acylcarnitine Analogues. Curr Pharm Design 2005;
11(29): 3757-3767.
[4] Rubinstein, A. Preclinical Studies of Alkylureas as Anti-HIV
Contraceptive and Non-Contraceptive Vaginal Microbicides.
Curr Pharm Design 2005; 11(29): 3769-3778.
[5] Silvestri, R., Artico, M. Indolyl Aryl Sulfones (IASs):
Development of Highly Potent NNRTIs Active Against wt-HIV-1
and Clinically Relevant Drug Resistant Mutants. Curr Pharm
Design 2005; 11(29): 3779-3806.
Keykavous Parang
Department of Biomedical and
Pharmaceutical Sciences
College of Pharmacy
University of Rhode Island
Kingston, RI 02881
USA
[Back to top]
Microbicides for Prevention of Transmission of Sexually
Transmitted Diseases
Mary K. Howett and Jeffrey P. Kuhl
In the last 50 years, changes in cultural and scientific
realities and customs have resulted in a worldwide epidemic
of sexually transmitted diseases (STD). This is a multi-factorial
problem resulting in part from:
1) an increased permissiveness in sexual attitudes in the
Western world that results in earlier onset of intercourse
and increased numbers of partners and types of sex acts;
2) a global transportation network that facilitates contacts
and interactions between urban and rural areas as well as
be-tween countries resulting in migration and spread of infections;
3) an emergence of new and mutated forms of pathogens with
increased capabilities to cause infections and for which there
are no available vaccines or therapies; and,
4) at risk populations in developing countries who are susceptible
to these pathogens while having societal infrastruc-tures
that lack basic health education and proper access to healthcare.
Overwhelming examples of increasing and emerging STD pathogens
exist in the early twenty-first century. These include human
immunodeficiency virus type 1 (HIV-1), the causative agent
of acquired immunodeficiency syndrome (AIDS), with over 42
million current cases of infection, 20 million deaths to date,
and an estimated 500,000 deaths per year; human papillomavirus
(HPV) infections, the causative agents of genital warts and
cervical cancer, with approximately 1 in 4 women harboring
virus DNA in genital epithelium, 1-3 percent of women showing
symptoms of infection and 250,000 deaths per year in women
worldwide from cervical cancer; and numerous others.
Topical microbicides have been proposed as agents to break
the chain of transmission in these infections by providing
chemical, biological, and/or physical barriers to infection
by blocking and/or inactivating pathogens at the mucosal surface
where infection can occur. For many sexually transmitted infections,
vaccines do not exist, and therapeutic agents are only partially
effective, expensive, and difficult to distribute. In addition,
female partners in many relationships do not control pregnancy
or STD risk and may benefit from discrete methods, other than
condoms, that would provide protection. Thus, microbicides
should be valuable additions to preventing these diseases
if they can be shown effective.
Currently, 62 microbicides are in development with 6 entering
Phase III clinical trials, 11 entering Phase I clinical trials,
and 44 in pre-clinical development. In this review, we will
describe many of the principles of microbicide mechanisms
and give examples of major types of microbicides and their
actions. Space precludes a complete description of all of
the agents and their mechanisms of action. We will also put
forth the argument for alkyl sulfate microbicides, including
sodium dodecyl sulfate (SDS), agents that are in active development
in our laboratories.
[Back to top]
Anti-HIV-1 Microbicides – ‘Chemical Condoms’
Designed to Limit the Scourge of the HIV-1 Pandemic
Stephen J. Scholand, Joseph A. DeSimone and Roger J. Pomerantz
The HIV pandemic continues to spread throughout the world,
particularly affecting populations in developing countries.
Women now comprise half of those infected. Efforts to limit
this scourge need to be maximally implemented. A multi-faceted
approach, including the research and advance of microbicides
– or ‘chemical condoms’ – offers promise.
Mi-crobicides are self-administered, prophylactic products
designed to protect against sexually transmitted pathogens,
includ-ing HIV-1. Important features include safety, efficacy
and user acceptability. This review summarizes some of the
impor-tant products in the development pipeline.
[Back to top]
Toward a Design of Affordable, Topical Microbicides:
Acylcarnitine Analogues
Richard D. Gandour
Most heterosexual women want to reduce the risk of acquiring
a sexually transmitted infection; many also want to control
their fertility. Several chemical agents have been proposed
to dramatically slow the spread of HIV infections. Ideally,
vaginal microbicides, with or without contraceptive properties,
should be safe, effective, and affordable for women everywhere.
Amphiphiles, which are surfactants that can act as detergents,
have a long history as microbicides against many pathogens.
Amphiphiles have several desirable traits; e.g., they are
inexpensive, fast-acting, and capable of a broad spectrum
of activity. An “ideal” amphiphilic microbicide
will rapidly and selectively inactivate pathogens and sperm
without irritating tissue. In this review, we discuss a homologous
series of amphiphilic acylcarnitine analogues as microbi-cides.
Two homologues, Z-14 and Z-15,
possess excellent spermicidal, anti-HIV, anti-chlamydial,
anti-gonorrhea, and anti-Haemophilus activities; both have
outstanding anti-Candida activity. A 4% Z-15
gel that is comprised of 3% carboxy-methylcellulose in water
gives a dramatically low score in a rabbit-vaginal-irritation
study. The mechanisms of action of these compounds are not
fully understood as yet, but we present several possibilities.
Moreover, the results of our limited structure-activity study
with a homologous series have stimulated additional questions
and ideas for designing the next generation of microbicidal
amphiphiles. The above studies support the idea that
Z-14 and Z-15 can potentially serve
as safe (non-irritating), effective topical microbicides.
[Back to top]
Preclinical Studies of Alkylureas as Anti-HIV-1 Contraceptive
Arye Rubinstein
The HIV-1 epidemic continues to spread at a rate of over
15, 000 new cases daily. HIV-1 transmission through heterosexual
contact became the dominant risk for women globally. About
half of the over 40 million HIV-1 infected indi-viduals worldwide
are now women. The lack of empowerment of women is the fundamental
cause for the rampant spread of HIV-1 in women. Topical microbicides
applied intravaginally offer an option for female-initiated
HIV-1 prevention. There is an urgent need to develop microbicides
with and without contraceptive qualities to also address socio-cultural
set-tings where the woman’s status is linked to fertility.
A safe and efficacious anti-HIV-1 vaginal formulation is
not yet available though a large number of candidates are
in pre-clinical or clinical studies. Presently marketed topical
microbicides are by and large toxic and damage the vaginal
mucosa with frequent use.
The microbicidal system of alkylureas evaluated here lends
itself to contraceptive and non-contraceptive anti- HIV-1
for-mulations.
Alkylureas are agents that irreversibly disrupt free and intracellular
HIV-1, have a wide margin of safety and are spermi-cidal above
their virucidal concentration without any mucosal toxicity.
Butylurea, the lead compound is also effective against other
sexually transmitted diseases (STDs) while sparing the normal
vaginal flora. Alkylureas with longer alkyl chains still have
to be explored and may have a greater selective microbicidality.
[Back to top]
Indolyl Aryl Sulfones (IASs): Development of Highly
Potent NNRTIs Active Against wt-HIV-1 and Clinically Relevant
Drug Resistant Mutants
Romano Silvestri and Marino Artico
Indolyl aryl sulfones (IASs) are a potent class of NNRTIs
developed from L-737,126, a lead agent discovered by Merck
AG. IAS derivatives are endowed with inhibitory activities
against wt HIV-1 in the low nanomolar concentration range.
Introduction of two methyl groups at positions 3 and 5 of
the phenyl ring of the aryl sulfonyl moiety furnished IAS
derivatives such as 5-chloro- or 5-bromo-3- [(3,5-dimethylphenyl)sulfonyl]
indole-2-carboxyamide, which showed very potent and selective
anti-HIV-1 activity against some mutants carrying NNRTI resistant
mutations at positions 103 and 181 of the reverse transcriptase.
IAS derivatives bearing 2-hydroxyethylcarboxyamide or 2-hydroxyethylcarboxyhydrazide
groups at position 2 of the indole nucleus were more active
than L-737,126 against the K103N-Y181C double mutant. A great
improvement of antiviral activity against wt HIV-1 and resistant
mutants was obtained by coupling 1-3 simple amino acids, such
as glycine and alanine, in sequence, with the 3-[(3,5-dimethylphenyl)sulfonyl]-
1H-indole-2-carbonyl moiety. The transformation of
the chain terminus into amide or hydrazide, produced short
peptides with high selectivity and potent activity against
wt HIV-1, and the viral mutants Y181C, K103N-Y181C and EFVR.
IAS having two halogen atoms at the indole showed potent inhibitory
activity against the Y181C and the EFVR resistant
mutant strains. In particular, the introduction of a fluorine
atom at position 4 of the indole ring notably contributed
to improve the antiviral activities against both wt and the
related resistant mutants. 5-Nitro-IASs were highly active
against wt HIV-1 and exhibited low cytotoxicity. Experimental
data highlighted the class IAS derivatives as promising candidates
for clinical trials.
[Back to top]
Ubiquitin-Proteasome Pathway Components as Therapeutic
Targets for CNS Maladies
Sudarshan C. Upadhya and Ashok N. Hegde
In the central nervous system (CNS), abnormal deposition
of insoluble protein aggregates or inclusion bodies within
nerve cells is commonly observed in association with several
neurodegenerative diseases. The ubiquitinated protein aggregates
are believed to result from malfunction or overload of the
ubiquitin-proteasome pathway or from structural changes in
the protein substrates which prevent their recognition and
degradation by the ubiquitin-proteasome pathway. Impaired
proteolysis might also contribute to the synaptic dysfunction
seen early in neurodegenerative diseases because the ubiquitin-proteasome
pathway is known to play a role in normal functioning of synapses.
Because specificity of the ubiquitin proteasome mediated proteolysis
is determined by specific ubiquitin ligases (E3s), identification
of specific E3s and their allosteric modulators are likely
to provide effective therapeutic targets for the treatment
of several CNS disor-ders. Another unexplored area for the
discovery of drug targets is the proteasome. Although many
inhibitors of the protea-some are available, no effective
drugs exist that can stimulate the proteasome. Since abnormal
protein aggregation is a common feature of different neurodegenerative
diseases, enhancement of proteasome activity might be an efficient
way to remove the aggregates that accumulate in the brain.
In this review, we discuss how the components of the ubiquitin-proteasome
pathway could be potential targets for therapy of CNS diseases
and disorders.
[Back to top]
Drug Tissue Distribution: Study Methods and Therapeutic
Implications
J.M. Lanao and M.A. Fraile
Current interest in studies on tissue distribution stems
from the limited capacity to predict tissue concentrations
and the pharmacological response from plasma drug levels,
and from the limitations – both methodological and deontological-
involved in doing so, especially in humans. In this review
we carry out a comparative analysis of the methods used for
studying tissue distribution, placing special focus on recently
developed non-invasive methods for the research of tissue
distribution in humans, such as positron emission tomography
and nuclear magnetic resonance spectroscopy. We describe the
strategies of tissue distribution pharmacokinetic analysis
that have evolved from analysis based on compartment and physiological
models to analyses based on spatial and fractal models and,
mainly, pharmacokinetic-pharmacodynamic models. Model-independent
analysis based on the use of mean transit times or deconvolution
strategies has become a good alternative for the pharmacokinetic
analysis of tissue distribution. The need to increase the
selectivity of many drugs justi-fies the desire to gain further
insight into the design of new analogues prodrugs and carrier
systems that will guarantee the specific delivery of a given
drug to a particular organ or tissue, optimising the response.
In silico models for drug distribu-tion have become a
helpful tool in drug discovery and development. The therapeutic
implications of drug tissue distribu-tion are also analysed,
special reference being made to antiretroviral therapy and
antitumoural gene therapy, among others.
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The Antiviral Activity, Mechanism of Action, Clinical
Significance and Resistance of Abacavir in the Treatment of
Pediatric AIDS
Joel Melroy and Vasu Nair
The novel carbocyclic nucleoside, abacavir, is metabolized
in cells to carbovir triphosphate which is a potent inhibitor
of HIV reverse transcriptase (Ki
0.021 μM with calf thymus DNA template primer).
Abacavir exhibits potent in vitro antiviral activity against
wild-type HIV-1 (IC50 4.0 μM, MT-4 cells)
but this activity is lower than the activity of AZT (IC50
0.040 μM, MT-4 cells). However, there is no significant
difference between the levels of activity of abacavir (IC50
0.26 μM) and AZT (IC50 0.23 μM) against
clinical isolates of HIV-1. The in vitro toxicity
data (CC50) of abacavir were: 160 μM (CEM
cells); 140 μM (CD4+ CEM cells) and 110 μM (normal
bone progenitor cells, BFU-E). Abacavir has been approved
in the United States for the treatment of pediatric and adult
HIV infection and current recommendations consist of combination
therapy in children with HIV infection. Resistance to abacavir
develops relatively slowly, with most of the mutations conferring
minimal resistance. The M184V mutation appears to be the cornerstone
of higher level resistance in regimens containing abacavir,
imparting a 2-4 fold reduction in the susceptibility of HIV
to abacavir.
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