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Microbicide Drug Candidates Including Cyanovirin-N To
Prevent Anal & Vaginal HIV Transmission
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"Cyanovirin-N Shows Potential to Block HIV Transmission"
Reuters Health Information Services (05/08/00)
A research team led by Dr. Edward Berger of the National Institute of Allergy
and Infectious Diseases has found that the protein cyanovirin-N (CV-N) blocks
steps when HIV interacts with specific target cell receptors. The findings,
published in the Journal of Virology, were based on the antiviral protein
because it can inactivate strains of HIV-1. Berger stated that CV-N could be used
to prevent HIV during sex. The protein could also be used to fight other
pathogens.
Biosyn, Inc. Announces $10 Million Grant from NIH: Cyanovirin-N
-Alliance News Flash- November 05, 2002M
Biosyn, Inc. Announces $10 Million Grant from National Institutes of
Health Huntingdon Valley, PA, November 4th, 2002 - Biosyn, Inc. announced
today that the company, along with five collaborating partners, has been
awarded a $10 million grant from the National Institutes of Health
(NIH)for the development of a potent HIV-inhibiting compound,
Cyanovirin-N, as a microbicide to prevent the sexual transmission of
HIV/AIDS. The collaborating institutions include The University of
Pennsylvania, Duke
University, TherImmune Research Corporation, Southern Research Institute,
and St. George's Hospital Medical School, U.K. The funding will be used
to advance Cyanovirin-N (CV-N) through pre-clinical development and, upon
filing of an Investigational New Drug application with the Food & Drug
Administration, initiation of clinical trials investigating the safety and
efficacy of CV-N in preventing HIV transmission. The grant covers a
period of five years.
CV-N is a novel protein isolated from the cyanobacterium, Nostoc
ellipsosporum (blue-green algae), and was discovered as part of an NIH
effort to identify and develop new classes of natural compounds that
inhibit the infectivity or cytopathic effects of HIV. Studies conducted on
CV-N to date have demonstrated the compound's activity against HIV and
potential use as a microbicide. Positive outcomes of this early research
include a primate model in which CV-N was shown to prevent vaginal and
rectal transmission of simian-human immunodeficiency virus (SHIV), an
HIV-like virus that infects monkeys.
"As an HIV-fusion inhibitor, Cyanovirin-N has remarkably potent HIV
activity and is an integral compound within our microbicide
portfolio.CV-N's potential as a microbicide to prevent HIV transmission
has been clearly established through both in vitro study of its activity
against HIV and animal prevention models," stated Dr. Richard Bax, Vice
President
and Chief Scientific Officer of Biosyn. "The significant support the NIH
is providing to us also makes evident the promise of this product. We are
extremely enthusiastic about having the ability to progress CV-N forward
along with the other compounds in our strong portfolio of microbicides."
Biosyn is developing a number of microbicides for the prevention of HIV
and other sexually transmitted diseases (STDs) including chlamydia,
genital herpes and papilloma virus. Each of these compounds is in a
different stage of development, with the company's leading microbicide
candidate, Savvy (1.0% C31G vaginal gel) entering Phase III clinical
trials early in 2003 for contraception, HIV prevention, and prevention of
other STDs.
Biosyn's receipt of the $10 million grant from the NIH not only ensures
the swift progression of CV-N into clinical trials, it is also validation
of the company's strategy to develop multiple microbicide candidates in
parallel, with the goal of bringing to market one or more microbicides as
expeditiously as possible over the next several years. With over 5.3
million people having acquired HIV in the year 2001 alone, there is an
urgent need for a microbicide to curb the onslaught of this pandemic as
well as provide women with a means of protecting themselves from STDs.
About Biosyn
Biosyn is a specialty pharmaceutical company focused on the development
and commercialization of novel drugs for infectious disease and
reproductive health. The Company's robust pipeline is anchored by a lead
candidate entering Phase III trials for STD prevention with excellent
clinical safety and efficacy data. Additionally, Biosyn's product
portfolio offers significant competitive advantages in areas where there
is a critical need for new or alternative therapies. In addition to its
microbicide portfolio, the company has product development ongoing in
several areas including oral complications of immuno-suppression, skin and
soft tissue infections, and ophthalmic infections.
Contact:
Kathryn LaMaina
Senior Manager Corporate Development
Tel: (215) 914-0900
Email: khl@biosyn-inc.com
The microbicide cyanovirin-N expressed on the surface of commensal bacterium
Streptococcus gordonii captures HIV-1.
AIDS. 2002 Jul 5;16(10):1351-6.
Giomarelli B, Provvedi R, Meacci F, Maggi T, Medaglini D, Pozzi G, Mori T,
McMahon JB,
Gardella R, Boyd MR.
Laboratory of Molecular Microbiology and Biotechnology, Department of
Molecular Biology, University of Siena, Siena, Italy.
OBJECTIVE: To explore the feasibility of expressing the potent
HIV-inactivating protein, cyanovirin-N (CV-N), in the human commensal bacterium
Streptococcus gordonii, as a possible approach for local delivery of CV-N to prevent
sexual transmission of HIV-1.
DESIGN AND METHODS: To express CV-N in S. gordonii, we used the host-vector
system we had previously developed. CV-N was expressed as a fusion protein
both attached to the bacterial surfaceand secreted in soluble form in the
supernatant of liquid cultures. The soluble form of recombinant CV-N was tested for
gp120-binding activity in an enzyme-linked immunosorbent assay, whereas S.
gordonii strain expressing CV-N on the surface was analyzed in an in vitro HIV
capturing assay.
RESULTS: Two recombinant S. gordonii strains secreting or displaying CV-N on
the bacterial surface were constructed and the expression of CV-N was
confirmed by immunoblot and flow-cytometric analysis. The secreted form of recombinant
CV-N exhibited a concentration-dependent binding to the envelope glycoprotein
gp120 of HIV-1, whereas CV-N displayed on the bacterial surface was able to
capture HIV virions efficiently.
CONCLUSION: The anti-HIV protein CV-N in S. gordonii was expressed in a
biologically active form. This represents a first step in the development of a
system to deliver and maintain an effective concentration of a microbicide in the
vaginal mucosa.
Cyanovirin-N Gel as a Topical Microbicide Prevents Rectal Transmission of
SHIV89.6P in Macaques
AIDS Research and Human Retroviruses Volume: 19 Number: 7 Page: 535-541
Author(s): Che-Chung Tsai ; Peter Emau ; Yonghou Jiang ; Baoping Tian ;
William R. Morton ; Kirk R. Gustafson ; Michael R. Boyd
Abstract:
Cyanovirin-N (CV-N), an 11-kDa cyanobacterial protein, potently inactivates
diverse strains of HIV-1, HIV-2, and simian immunodeficiency virus (SIV) and
also prevents virus-to-cell fusion, virus entry, and infection of cells in
vitro. These properties make CV-N an attractive candidate for use as a topical
microbicide to prevent the sexual transmission of HIV.
We evaluated the efficacy of gel-formulated, recombinant CV-N gel as a
topical microbicide in male macaques (Macaca fascicularis) that were rectally
challenged with a chimeric SIV/HIV-1 virus known as SHIV89.6P.
All of the untreated macaques were infected and experienced CD4+ T cell
depletion. In contrast, none of the macaques that received either 1% or 2% CV-N gel
showed evidence of SHIV89.6P infection. Neither CV-N nor placebo gels pro
duced any adverse effects in any macaque following the rectal application. These
results indicate that CV-N gel as a topical microbicide can prevent rectal
transmission of SHIV in macaques. These studies encourage clinical evaluation of
CV-N as a topical microbicide to prevent sexual transmisision of HIV in
humans.
"Cyanovirin-N, a Potent Human Immunodeficiency Virus-Inactivating Protein,
Blocks both
CD4-Dependent and CD4-Independent Binding ofSoluble gp120 (sgp120) to Target
Cells, Inhibits sCD4-Induced Binding of sgp120 to Cell-Associated CXCR4, and
Dissociates Bound sgp120 from Target Cells"
Antimicrob Agents Chemother. 2001 March; 45 (3): 664–672
Toshiyuki Mori and Michael R. Boyd*
Laboratory of Natural Products, Division of Basic Sciences, National Cancer
Institute-Frederick, Cancer Research and Development Center, Frederick,
Maryland
21702
Cyanovirin-N (CV-N), an 11-kDa protein originally isolated from the
cyanobacterium Nostoc
ellipsosporum, potently inactivates diverse strains of human immunodeficiency
virus type 1 (HIV-1), HIV-2, simian immunodeficiency virus, and feline
immunodeficiency virus. It has been well established that the HIV surface envelope
glycoprotein gp120 is a molecular target of CV-N. We recently reported that
CV-N impaired the binding of virion-associated gp120 to cell-associated CD4 and
that CV-N preferentially inhibited binding of the glycosylation-dependent
neutralizing monoclonal antibody 2G12 to gp120. However, CV-N did not interfere
with the interactions of soluble CD4 (sCD4) with either soluble gp120 (sgp120) or
virion-associated gp120. In the present study, we have evaluated the effects
of CV-N on the binding of sgp120 to cell-associated CD4 to clarify the
experimental basis of the previous binding results, and we further address the
detailed mechanism of action of CV-N.
Here we present evidence that (i) CV-N impairs both CD4-dependent and
CD4-independent binding of sgp120 to the target cells, (ii) CV-N blocks the
sCD4-induced binding of sgp120 with cell-associated coreceptor CXCR4, and (iii) CV-N
dissociates bound sgp120 from target cells. The results illustrate that the
measured effects of CV-N on gp120-CD4 binding interactions depend upon the type of
CD4 (soluble or cell associated), but not upon the type of gp120 (soluble or
virion associated), employed in the experimental protocol. In addition, this
study reinforces that CV-N acts uniquely to prevent essential interactions
between the envelope glycoprotein and target cell receptors and further supports
the potential broad utility of CV-N as a microbicide to prevent the
transmission of HIV and AIDS.
Research on Vaginal Microbicides in India
-By Bobby Ramakant, India
HDN Key Correspondent
Indian National Workshop on Prevention Options for Women: Female Condoms
and Microbicides
October 2002, New Delhi
>From a cohort study conducted by the apex research body on HIV/AIDS in
India - National AIDS Research Institute (NARI), a unit of ICMR (Indian
Council of Medical Research) - Dr. Smita Joshi, senior Research Officer,
said that HIV epidemic is not only restricted to persons with high risk
behaviour but has also reached women with no risk behaviour of their own.
Dr Joshi was speaking at the recently held PATH/IN N workshop on
Prevention Options for Women in New Delhi.
Sentinel surveillance study conducted by NARI in Pune has shown a steady
rise in HIV sero-prevalence in pregnant women attending government
ante-natal clinics. Dr. Joshi stated that majority of married monogamous
women get HIV and STDs from their spouses. HIV prevalence in monogamous
married women of male STD patients surveyed by NARI, was 18%. Condom use
by men with sex workers increased over time, but more than 75% men never
used condoms with non-sex worker partners and their spouses.
This sharply reveals the vulnerability of Indian women to STDs including
HIV/AIDS, especially those who are monogamous and may not be classified as
'high-risk' populations.
The negligible or no use of male condoms by male STD patients with their
non sex-worker partners or spouses in the NARI study, stands out in sharp
contrast to the increasing use of male condoms by the same male STD
patients with sex workers. This further increases the vulnerability of
monogamous married women who usually fall outside the orbit of high-risk
population evident by the steadily rising HIV incidence and prevalence
rates in this population. Dr. Smita Joshi said that this makes it all the
more vital to have options which women can use themselves.
Speaking about Microbicides candidate products that NARI ran Phase II
trials on, she said that Buffer Gel clinical trials were multi-centric and
multi-national in nature and were conducted in US (Rhode Island), Thailand
(Chiang Mai), Zimbabwe (Harare), Malawi (Blantyre) and India (Pune).
Buffer Gel 'acidifies' the vagina by lowering vaginal pH and at a 5 ml
dose is capable of neutralizing 3 times the volume of a normal ejaculate.
Commenting on the acceptability of buffer gel by trial participants, she
said that physical characteristics, like lack of colour and smell, didn't
pose any problems. However they did feel that the formulation of buffer
gels should be 'thicker'. Leakage of the product, use of applicators and
problems in disposal of condoms were some of the concerns of the
participating women.
Dr. Smita Joshi said that women do perceive that they are at risk of
getting infected with STD/HIV from their spouses and are willing to try
products that can protect them.
She was hopeful that Phase II and Phase III trials especially in women
with high risk behaviour would provide additional evidence on toxicity and
efficacy.
She said that the major issues raised by participating female sex workers
in microbicides clinical trials were about the false sense of security
such products may give and it's availability at an affordable price after
the effectiveness studies.
Phase III trials are expected to begin mid-2003 in India.
Bobby Ramakant
HDN Key Correspondent
E-mail: correspondents@hdnet.org
E-mail: bobbyramakant@hotmail.com
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